Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases

ABSTRACT

The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor. Although a wide range of COX-II inhibitors may be employed but it is preferred to employ compounds of the Formula I: ##STR1##

RELATED US APPLICATION DATA

This is a continuation in part of U.S. Ser. No. 08/539,930 filed Oct. 6,1995 which is a continuation in part of co-pending U.S. Ser. No.08/461,783 filed Jun. 5, 1995 which is a continuation-in-part of Ser.No. 08/179,467 filed Jan. 10, 1994 which is a continuation-in-part ofU.S. Ser. No. 08/082,196 filed Jun. 24, 1993. This application is also aContinuation-in-Part of U.S. Ser. No. 08/152,620, filed Nov. 12, 1993(now U.S. Pat. No. 5,436,265) and U.S. Ser. No. 08/147,804 filed Nov. 4,1993 (Now U.S. Pat. No. 5,604,260).

BACKGROUND TO THE INVENTION

U.S. Pat. No. 5,192,753 states inter alia that dementia in human beingsmay be treated with compounds selected from the non-steroidalanti-inflammatory group of cyclooxygenase inhibitors. The non-steroidanti-inflammatory drugs (NSAIDs) referred to in U.S. Pat. No. 5,192,753are all agents which possess significant ability to inhibitcyclooxygenase type 1 (COX-1). A number of publications have alsooccurred in the scientific literature which disclose that agents such asacetylacetic acid and indomethecin, which are generally viewed as potentinhibitors of COX- 1, can be used in the treatment of Alzheimersdisease; see for example:

McGeer et al, Lancet, 1990:335, 1037;

Rogers et al, Neurology, 1993:43; 1609-1611;

McGeer et al, Neurology, 1992:42, 447-449; and

Breitner et al, Neurology, 1994, 227-232.

Cyclooxygenase (COX) exists in the human as cyclooxygenase type I(COX-I) and cyclooxygenase type II (COX-II also referred to herein asCOX-2). Hitherto there has been no suggestion that COX-II plays any rolein Alzheimers disease. Indeed there has been no evidence whichdemonstrates that COX-II plays a part in any human central nervoussystem disorder. COX-II is inducilible by a number of agents such asmitogen, endotoxin, cytokines and the like but none of these agentswhich have been demonstrated as inducing COX-II have been shown to becausitive in Alzheimers disease.

Non-steroidal, antiinflammatory drugs exert most of theirantiinflammatory, analgesic and antipyretic activity and inhibithormone-induced uterine contractions and certain types of cancer growththrough inhibition of prostaglandin G/H synthase, also known ascyclooxygenase. Up until recently, only one form of cyclooxygenase hadbeen characterized, this corresponding to cyclooxygenase-1 or theconstitutive enzyme, as originally identified in bovine seminalvesicles. Recently the gene for a second inducible form ofcyclooxygenase (cyclooxygenase-2) has been cloned, sequenced andcharacterized from chicken, murine and human sources. This enzyme isdistinct from the cyclooxygenase-1 which has now also been cloned,sequenced and characterized from sheep, murine and human sources. Thesecond form of cyclooxygenase, cyclooxygenase-2, is rapidly and readilyinducible by a number of agents including mitogens, endotoxin, hormones,cytokines and growth factors. As prostaglandins have both physiologicaland pathological roles, we have concluded that the constitutive enzyme,cyclooxygenase-1, is responsible, in large part, for endogenous basalrelease of prostaglandins and hence is important in their physiologicalfunctions such as the maintenance of gastrointestinal integrity andrenal blood flow. In contrast, we have concluded that the inducibleform, cyclooxygenase-2, is mainly responsible for the pathologicaleffects of prostaglandins where rapid induction of the enzyme wouldoccur in response to such agents as inflammatory agents, hormones,growth factors, and cytokines. Thus, a selective inhibitor ofcyclooxygenase-2 will have similar antiinflammatory, antipyretic andanalgesic properties to a conventional non-steroidal antiinflammatorydrug, and in addition would inhibit hormone-induced uterine contractionsand have potential anti-cancer effects, but will have a diminishedability to induce some of the mechanism-based side effects. Inparticular, such a compound should have a reduced potential forgastrointestinal toxicity, a reduced potential for renal side effects, areduced effect on bleeding times and possibly a lessened ability toinduce asthma attacks in aspirin-sensitive asthmatic subjects.

The present invention provides a method of treating a neurodegenerativedisease and in particular Alzheimers disease which comprisesadministering to a human in need thereof a therapeutically effectiveamount of a non-steroid COX-II inhibitor.

SUMMARY OF INVENTION

The present invention provides a method of treating a neurodegenerativedisease and in particular Alzheimers disease which comprisesadministering to a human in need thereof a therapeutically effectiveamount of a non-steroid COX-II inhibitor. Although a wide range ofCOX-II inhibitors may be employed but it is preferred to employcompounds of the Formula I as set out hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention encompasses a method of treating aneurodegenerative disease in a human which comprises administering tosaid human an effective amount of a non-steroidal COX-2 inhibitor.

Within this apsect the invention encompasses a method of treating theneurodegenerative disease, Alzheimers Disease.

Within the above aspect the invention also encompasses a method oftreating stroke, cerebral ischemia and de-myelinating disorders.

Oral administration (such as by tablet or capsule) is a preferred modeof administration.

Within the above aspect, there is a preferred class of method whereinthe non-steroidal COX-2 inhibitor will bind at least 100 times as wellto COX-2 as to COX-1.

Within the above aspect there is a preferred class of COX-2 inhibitors,which is:

(a)3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene,

(b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,

(c)3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene,

(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene,

(e) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylic acid,

(f) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole,

(g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one

(h) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)isothiazole,

(i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(j) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone,

(k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl) furan,

(l) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(m) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl) thiophene,

(n)3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,

(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(p) 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(q) 5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(t)5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(u)5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(v)5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(w) 3-(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(x) 5,5-Dimethyl-3-(2-naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, and

(y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.

The invention also encompasses the novel compound of Formula I useful inthe treatment of cyclooxygenase-2 mediated diseases ##STR2## orpharmaceutically acceptable salts thereof wherein: X--Y--Z-- is selectedfrom the group consisting of:

(a) --CH₂ CH₂ CH₂ --,

(b) --C(O)CH₂ CH₂ --,

(c) --CH₂ CH₂ C(O)--,

(d) --CR⁵ (R^(5'))--O--C(O)--,

(e) --C(O)--O--CR⁵ (R^(5'))--,

(f) --CH₂ --NR³ --CH₂ --,

(g) --CR⁵ (R^(5'))--NR³ --C(O)--,

(h) --CR⁴ ═CR^(4') --S--,

(i) --S--CR⁴ ═CR^(4') --,

(j) --S--N═CH--,

(k) --CH═N--S--,

(l) --N═CR⁴ --O--,

(m) --O--CR4=N--

(n) --N═CR⁴ --NH--;

(o) --N═CR⁴ --S--, and

(p) --S--CR⁴ ═N--;

(q) --C(O)--NR³ --CR⁵ (R^(5'))--;

(r) --R³ N--CH═CH-- provided R¹ is not --S(O)₂ Me

(s) --CH═CH--NR³ -- provided R¹ is not --S(O)₂ Me

when side b is a double bond, and sides a an c are single bonds; and

X--Y--Z-- is selected from the group consisting of:

(a) ═CH--O--CH═, and

(b) ═CH--NR³ --CH═,

(c) ═N--S--CH═,

(d) ═CH--S--N═,

(e) ═N--O--CH═,

(f) ═CH--O--N═,

(g) ═N--S--N═,

(h) ═N--O--N═,

when sides a and c are double bonds and side b is a single bond;

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NH₂,

(c) S(O)₂ NHC(O)CF₃,

(d) S(O)(NH)CH₃,

(e) S(O)(NH)NH₂,

(f) S(O)(NH)NHC(O)CF₃,

(g) P(O)(CH₃)OH, and

(h) P(O)(CH₃)NH₂,

R² is selected from the group consisting of

(a) C₁₋₆ alkyl,

(b) C₃, C₄, C₅, C₆, and C₇, cycloalkyl,

(c) mono-, di- or tri-substituted phenyl or naphthyl wherein thesubstituent is selected from the group consisting of

(1) hydrogen,

(2) halo,

(3) C₁₋₆ alkoxy,

(4) C₁₋₆ alkylthio,

(5) CN,

(6) CF₃,

(7) C₁₋₆ alkyl,

(8) N₃,

(9) --CO₂ H,

(10) --CO₂ --C₁₋₄ alkyl,

(11) --C(R⁵)(R⁶)--OH,

(12) --C(R⁵)(R⁶)--O--C₁₋₄ alkyl, and

(13) --C₁₋₆ alkyl-CO₂ --R⁵ ;

(d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is amonocyclic aromatic ring of 5 atoms, said ring having one hetero atomwhich is S, O, or N, and optionally 1, 2, or 3 additionally N atoms; orthe heteroaryl is a monocyclic ring of 6 atoms, said ring having onehetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms;said substituents are selected from the group consisting of

(1) hydrogen,

(2) halo, including fluoro, chloro, bromo and iodo,

(3) C₁₋₆ alkyl,

(4) C₁₋₆ alkoxy,

(5) C₁₋₆ alkylthio,

(6) CN,

(7) CF₃,

(8) N₃,

(9) --C(R⁵)(R⁶)--OH, and

(10) --C(R⁵)(R⁶)--O--C₁₋₄ alkyl;

(e) benzoheteroaryl which includes the benzo fused analogs of (d);

R³ is selected from the group consisting of

(a) hydrogen,

(b) CF₃,

(c) CN,

(d) C₁₋₆ alkyl,

(e) hydroxyC₁₋₆ alkyl,

(f) --C(O)--C₁₋₆ alkyl,

(g) optionally substituted

(1) --C₁₋₅ alkyl-Q,

(2) --C₁₋₃ alkyl-O--C₁₋₃ alkyl-Q,

(3) --C₁₋₃ alkyl-S--C₁₋₃ alkyl-Q,

(4) --C₁₋₅ alkyl-O--Q, or

(5) --C₁₋₅ alkyl-S--Q,

wherein the substituent resides on the alkyl and the substituent is C₁₋₃alkyl;

(h) --Q

R⁴ and R^(4') are each independently selected from the group consistingof

(a) hydrogen,

(b) CF₃,

(c) CN,

(d) C₁₋₆ alkyl,

(e) --Q,

(f) --O--Q;

(g) --S--Q, and

(h) optionally substituted

(1) --C₁₋₅ alkyl-Q,

(2) --O--C₁₋₅ alkyl-Q,

(3) --S--C₁₋₅ alkyl-Q,

(4) --C₁₋₃ alkyl-O--C₁₋₃ alkyl-Q,

(5) --C₁₋₃ alkyl-S--C₁₋₃ alkyl-Q,

(6) --C₁₋₅ alkyl-O--Q,

(7) --C₁₋₅ alkyl-S--Q,

wherein the substituent resides on the alkyl and the substituent is C₁₋₃alkyl, and

R⁵, R^(5'), R⁶, R⁷ and R⁸ are each independently selected from the groupconsisting of

(a) hydrogen,

(b) C₁₋₆ alkyl,

or R⁵ and R⁶ or R⁷ and R⁸ together with the carbon to which they areattached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7atoms;

Q is CO₂ H, CO₂ --C₁₋₄ alkyl, tetrazolyl-5-yl, C(R⁷)(R⁸)(OH), or

C(R⁷)(R⁸)(O--C₁₋₄ alkyl);

provided that when X--Y--Z is --S--CR⁴ ═CR^(4'), then R⁴ and R^(4') areother than CF₃.

One Class within this embodiment are the compounds of formula I ##STR3##or pharmaceutically acceptable salts thereof wherein: X--Y--Z-- isselected from the group consisting of --C(O)--O--CR⁵ (R^(5'))-- whenside b is a double bond, and sides a and c are single bonds; and

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NH₂,

R² is selected from the group consisting of

(a) C₁₋₆ alkyl,

(b) C₃, C₄, C₄, C₅, C₆, and C₇, cycloalkyl,

(c) heteroaryl

(d) benzoheteroaryl

(e) mono- or di-substituted phenyl wherein the substituent is selectedfrom the group consisting of

(1) hydrogen,

(2) halo,

(3) C₁₋₆ alkoxy,

(4) C₁₋₆ alkylthio,

(5) CN,

(6) CF₃,

(7) C₁₋₆ alkyl,

(8) N₃,

(9) --CO₂ H,

(10) --CO₂ --C₁₋₄ alkyl,

(11) --C(R⁵)(R⁶)--OH,

(12) --C(R⁵)(R⁶)--O--C₁₋₄ alkyl, and

(13) --C₁₋₆ alkyl-CO₂ --R⁵ ;

R⁵, R^(5') and R⁶ are each independently selected from the groupconsisting of

(a) hydrogen,

(b) C₁₋₆ alkyl,

or R⁵ and R⁶ together with the carbon to which they are attached form asaturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.

For purposes of this specification alkyl is defined to include linear,branched, and cyclic structures, with C₁₋₆ alkyl including methyl,ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl,1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Similarly, C₁₋₆ alkoxy is intended to include alkoxy groups of from 1 to6 carbon atoms of a straight, branched, or cyclic configuration.Examples of lower alkoxy groups include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Likewise, C₁₋₆alkylthio is intended to include alkylthio groups of from 1 to 6 carbonatoms of a straight, branched or cyclic configuration. Examples of loweralkylthio groups include methylthio, propylthio, isopropylthio,cycloheptylthio, etc. By way of illustration, the propylthio groupsignifies --SCH₂ CH₂ CH₃.

Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole,pyrazole, oxazole, thiazole, imidazole, 1,2,3-oxadiazole,1,2,3-thiadiazole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,3,4-triazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, pyridine,pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine,1,2,4,5-tetrazine, and the like.

Benzoheteroaryl includes the above heteroaryl rings to which it ispossible to fuse a benzene ring.

Exemplifying the invention are:

(a)3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene,

(b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,

(c)3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene,

(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene,

(e)5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylicacid,

(f) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole,

(g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one

(h) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole,

(i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(j) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone,

(k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan,

(l)5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(m) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene, and

(n)3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,

(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(p)5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(q)5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(t)5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(u)5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(v)5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(w) 3-(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(x)5,5-Dimethyl-3-(2-naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

(y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention is meant to comprehend such possible diastereomers aswell as their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

In a second embodiment, the invention encompasses pharmaceuticalcompositions for inhibiting cyclooxygenase and for treatingcyclooxygenase mediated diseases as disclosed herein comprising apharmaceutically acceptable carrier and a non-toxic therapeuticallyeffective amount of compound of formula I as described above.

Within this embodiment the invention encompasses pharmaceuticalcompositions for inhibiting cyclooxygenase-2 and for treatingcyclooxygenase-2 mediated diseases as disclosed herein comprising apharmaceutically acceptable carrier and a non-toxic therapeuticallyeffective amount of compound of formula I as described above.

In a third embodiment, the invention encompasses a method of inhibitingcyclooxygenase and treating cyclooxygenase mediated diseases,advantageously treated by an active agent that selectively inhibitsCOX-2 in preference to COX-1 as disclosed herein comprising:administration to a patient in need of such treatment of a non-toxictherapeutically effective amount of a compound of Formula I as disclosedherein.

For purposes of this specification a compound is said to selectivelyinhibit COX-2 in preference to COX-1 if the ratio of the IC50concentration for COX-1 inhibition to COX-2 inhibition is 100 orgreater.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt, thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium, and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

The Compound of Formula I is useful for the relief of pain, fever andinflammation of a variety of conditions including rheumatic fever,symptoms associated with influenza or other viral infections, commoncold, low back and neck pain, dysmenorrhea, headache, toothache, sprainsand strains, myositis, neuralgia, synovitis, arthritis, includingrheumatoid arthritis degenerative joint diseases (osteoarthritis), goutand ankylosing spondylitis, bursitis, bums, injuries, following surgicaland dental procedures. In addition, such a compound may inhibit cellularneoplastic transformations and metastic tumor growth and hence can beused in the treatment of cancer. Compounds of formula I may also beuseful for the treatment of dementia including pre-senile and seniledementia, and in particular, dementia associated with Alzheimer Disease(ie Alzheimer's dementia).

Compounds of formula I will also be useful in the treatment of Stroke,cerebral ischemia and de-myelinating disorders.

Compounds of formula I will also inhibit prostanoid-induced smoothmuscle contraction by preventing the synthesis of contractileprostanoids and hence may be of use in the treatment of dysmenorrhea,premature labor and asthma.

By virtue of its high cyclooxygenase-2 (COX-2) activity and/or itsselectivity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1) asdefined above, compounds of formula I will prove useful as analternative to conventional non-steroidal antiinflammatory drugs(NSAID'S) particularly where such non-steroidal antiinflammatory drugsmay be contra-indicated such as in patients with peptic ulcers,gastritis, regional enteritis, ulcerative colitis, diverticulitis orwith a recurrent history of gastrointestinal lesions; GI bleeding,coagulation disorders including anemia such as hypoprothrombinemia,haemophilia or other bleeding problems (including those relating toreduced or impaired platelet function); kidney disease (eg impairedrenal function); those prior to surgery or taking anticoagulants; andthose susceptable to NSAID induced asthma.

Similarly, compounds of formula I, will be useful as a partial orcomplete substitute for conventional NSAID'S in preparations whereinthey are presently co-administered with other agents or ingredients.Thus in further aspects, the invention encompasses pharmaceuticalcompositions for treating cyclooxygenase-2 mediated diseases as definedabove comprising a non-toxic therapeutically effective amount of thecompound of Formula I as defined above and one or more ingredients suchas another pain reliever including acetominophen or phenacetin; apotentiator including caffeine; an H2-antagonist, aluminum or magnesiumhydroxide, simethicone, a decongestant including phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine;an antiitussive including codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; a sedating ornon-sedating antihistamine. In addition the invention encompasses amethod of treating cyclooxygenase mediated diseases comprising:administration to a patient in need of such treatment a non-toxictherapeutically effect amount of the compound of Formula I, optionallyco-administered with one or more of such ingredients as listedimmediately above.

Compounds of the present invention are inhibitors of cyclooxygenase-2and are thereby useful in the treatment of cyclooxygenase-2 mediateddiseases as enumerated above. This activity is illustrated by theirability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.Accordingly, in one assay, the ability of the compounds of thisinvention to treat cyclooxygenase mediated diseases can be demonstratedby measuring the amount of prostaglandin E₂ (PGE₂) synthesized in thepresence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and acompound of formula I. The IC50 values represent the concentration ofinhibitor required to return PGE₂ synthesis to 50% of that obtained ascompared to the uninhibited control. Illustrating this aspect, we havefound that the Compounds of the Examples are more than 100 times moreeffective in inhibiting COX-2 than they are at inhibiting COX-1. Inaddition they all have a COX-2 IC50 of 1 nM to 1 mM. By way ofcomparison, Ibuprofen has an IC50 for COX-2 of 1 mM, and Indomethacinhas an IC50 for COX-2 of approximately 100 nM. For the treatment of anyof these cyclooxygenase mediated diseases, compounds of formula I may beadministered orally, topically, parenterally, by inhalation spray orrectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques. Inaddition to the treatment of warm-blooded animals such as mice, rats,horses, cattle sheep, dogs, cats, etc., the compound of the invention iseffective in the treatment of humans.

As indicated above, pharmaceutical compositions for treatingcyclooxygenase-2 mediated diseases as defined may optionally include oneor more ingredients as listed above.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed with water oran oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethyl-cellulose, methylcellulose, hydroxy-propylmethycellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

Compounds of formula I may also be administered in the form of asuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

Dosage levels of the order of from about 0.01 mg to about 140 mg/kg ofbody weight per day are useful in the treatment of the above-indicatedconditions, or alternatively about 0.5 mg to about 7 g per patient perday. For example, inflammation may be effectively treated by theadministration of from about 0.01 to 50 mg of the compound per kilogramof body weight per day, or alternatively about 0.5 mg to about 3.5 g perpatient per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 g of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 800 mg, or 1000 mg.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

The present invention provides a method of treating a neurodegenerativedisease and in particular Alzheimers disease which comprisesadministering to a human in need thereof a therapeutically effectiveamount of a non-steroid COX-II inhibitor.

From another aspect this invention provides the use of a COX-IIinhibitor in the manufacture of a medicament for the treatment ofneurodegenerative diseases including dementia, and in particularAlzheimers disease. Risk factors include those based on Apo lipoproteingenotype, age, Mild Cognitive Impairment and family History.

When used herein the term "treating" includes treatment of existingdisease and prophylactic treatment of those at risk of developing thedisease.

When used herein the term "COX-II" inhibitor means a compound able toinhibit human COX-II enzyme without causing relatively significantinhibition of human COX-I enzyme. Generally compounds which bind atleast 10 times as well to COX-I receptors as to COX-II receptors (iewill have a IC₅₀ COX-II receptor only one tenth the numerical value ofthe COX-I receptor) are chosen for use in the invention, more aptly 20times as well, favourably 50 times as well most favourably at least 100times as well, and preferably at least 1000 times as well.

The COX-II inhibitors for use in this invention are most aptly thosewhich are highly brain penetrant so that the maximum concentration ofCOX-II inhibitor after administration of the anti-neurodegenerative forexample the anti-alzheimer effective dose of COX-II inhibitor is atleast the binding IC₅₀ value and preferably at least 10 times that valuefor example at least 100 times the binding IC₅₀ value.

The COX-II inhibitor may be of any structural type other than a steroid.However, most aptly the COX-II inhibitor employed in this invention isnot a carboxylic acid or a salt thereof. Most favourably it will possessa SO₂ CH₃, NHSO₂ CH₃, SO₂ NH₂, SO₂ NHCH₃ or like substituent on anaromatic ring especially on a phenyl ring.

Our investigations and statements made in the more recent of thefollowing patents indicate that COX-II inhibitors may be found in U.S.Pat. Nos. 4,375,479; 4,590,205; 4,820,827; 5,343,991; EP 0418845; WO91/19708; WO 94/15932 and WO 94/13635. Each of the above documents isincorporated herein by cross reference.

Thus in one aspect this invention provides a method of treating aneurodegenerative disease and in particular Alzheimers disease whichcomprises administering to a patient therapeutically effective amount ofa compound generically disclosed (and preferably a compound specificallydescribed) in U.S. Pat. Nos. 4,375,479; 4,590,205; 4,820,827; 5,344,991;EP 0418845; WO 91/19708; WO 94/15932 or WO 94/13635 all of which areincorporated herein by cross reference.

The invention also provides the use of such compounds in the manufactureof a medicament for the treatment of neurodegenerative disease and inparticular Alzheimers disease.

Favourably the COX-II inhibitor employed is one described in WO 94/26731(published Nov. 24, 1994), WO 94/20480 (published Sep. 15, 1994), U.S.Pat. No. 5,436,265 (issued Jul. 25, 1995), WO 95/00501 (published Jan.5, 1995) or WO 95/18799 (published Jul. 13, 1995) all of which areincorporated herein by cross reference.

The medicaments for treating neurodegenerative disease may be formulatedas described in the aforementioned referenced documents. The medicamentmay be employed in the doses and regimens set out in the aforementionedreferenced documents with respect to the treatment of diseases whichbenefit from the administration of a COX-II inhibitor.

It is a great advantage of this invention that treatment may be carriedout without causing gastric side effects of the type that can occur whenCOX I inhibitors are used for prolonged periods. Since neurodegenerativediseases such as Alzheimers disease are generally progressive treatmentmay need to take place for a number of years. Thus the provision ofmedicaments which are surprisingly effective without any significanttendency to cause gastric side effects at the therapeutic dose is ofgreat use particularly to the elderly. The use of medicaments of thisinvention for the treatment of patients who are asymptotic is alsoenvisaged especially in those cases where genetic information suggeststhat the patient is likely to develop Alzheimers disease or otherneurodegenerative disease especially those which may be termed dementia,for example senile dementia or pre-senile dementia.

Favourably this invention provides a method of treatingneurodegenerative disease without any significant tendency to causegastric side effects which comprises the oral administration of apharmaceutical composition which comprises an effective amount of aCOX-II inhibitor and a pharmaceutical acceptable carrier therefor.

Such a method is applicable to patients with overt symptoms of diseaseand is applicable without overt symptoms of the disease (asymptoticpatients).

Generally the oral dosage form will be administered from 1 to 6 timesper day. Preferably the oral dosage form will be administered once ortwice per day.

EXAMPLE

Using PCR analysis of mRNA extracted from the post-mortem hippocampus of7 AD patients and 6 age-matched control patients (with no history ofneurological or neuropsychiatric diseases, we found COX-II mRNA in 6 ADpatients. Four of the control patients showed no COX-II mRNA. In situhybridization histochemistry also showed COX-II mRNA in the hippocampusof 4 AD patients but not in 5 control patients. Western blot analysis oftemporal lobe cortex showed COX-II protein in 3AD patients but not in 3control patients.

These results show that COX-II is induced in the medial temporal lobe ofAD patients, a brain region most severely affected during alzheimersdisease process. The results indicate that the inflammatory conditionassociated with AD involve COX-II in its aetiology and show thattreating AD patients with brain penetrant selective COX-II inhibitorswill be effective.

Methods of Synthesis

The compounds of the present invention can be prepared according to thefollowing methods.

Method A

The b-chlorovinylaldehyde III can be obtained from the ketone II and theVilsmeier reagent (DMF-POCl₃) using the general method described byWeissenfels (Z. Chem. 1966, 6, 471). The thiophene compound IV isobtained from III using the general method described by Weissenfels (Z.Chem., 1973, 13, 57). The thiol compound V can be obtained afteroxidation of compound IV (R^(a) =--SMe) with one equivalent of m-CPBAfollowed by treatment of the resulting sulfoxide with TFAA at reflux.The sulfonamide group (VI) can then be formed by the method of Kharash(J. Amer. Chem. Soc. 1951, 73, 3240). The hydrolysis of compound VI anddecarboxylation with Cu bronze in quinoline provides compound VII.Compound VII (R⁴ ═H) can be treated with halogenating agent such asbromine in acetic acid to allow the preparation of the 5-bromothiophene(VII, R⁴ ═Br). When it is desired to have a nitrile group at C-5, thiscan be accomplished from VI via amide formation using the Weinrebmethodology (Tetrahedron Letters, 1977, 4171) followed by dehydrationwith TFAA. The CF₃ group can be introduced at C-5 of VII via the methodof Girard (J. Org. Chem. 1983, 48, 3220).

The introduction of an alkyl group at C-5 can be achieved via aFriedel-Crafts reaction on VII (R⁴ ═H) and an acyl chloride,Cl--CO-lower alkyl and a catalyst such as TiCl₄, followed by reduction.For R⁴ ═Me, this can be achieved from the ester (R⁴ ═CO₂ Me) via aDIBAL-H reduction followed by deoxygenation using the method of Lau (J.Org. Chem. 1986, 51, 3038). Tertiary alcohols (R⁴ =--C(CH₃)₂ OH) can beobtained from VI and MeMgBr. These tertiary alcohols can also bedeoxygenated using the method of Lau. Similarly, the thiophene IX can beprepared from ketone VIII. ##STR4## Method B

Ketone X can be converted to the thiophene compound XI using generalmethods already described in Method A. The thiophene XII can be preparedby metallation of XI with n-BuLi, quenching with methyl phosphonicdichloride and addition of water or ammonia (X'═OH or NH₂). Similarly,the other regioisomer XIV can be prepared from ketone XIII. ##STR5##Method C

Bromination of ketone II gives the a-bromoketone XV which is thenconverted to the thiazole XVI after treatment with a thioamide.Similarly, ketone VIII can be converted to thiazole XVII. ##STR6##Method D

Ketone XV can be converted to the imidazole compound XVIII aftertreatment with formamide using the preparation of Brederick et al, Chem.Ber. 1953, p. 88. ##STR7## Method E

Pyrole compound XX can be obtained from diketone XIX using the generalprocedures of Friedman et al, J. Org. Chem. 1965, 30, p. 854, K. Dimrothet al, Ber. 1956, 56, 2602, K. Dimroth et al, Ann. 1961, 634, 102. Thefree NH of the pyrole can be acylated with Cl--CO-lower alkyl in thepresence of a base such as Et₃ N. Also alkylated products can beprepared using alkyl halides as reagents with a base such as NaH.##STR8## Method F

The compounds of type XXV can be prepared from readily available4-substituted phenylacetyl chlorides XXIa. Reaction ofdi(3-butenyl)cadmium with a 4-substituted phenylacetyl chloride providesketone XXI. Ozonolysis of XXI affords keto aldehyde XXIb which iscyclized by base to give cyclopentenone XXII. Addition of arylmagnesiumbromide or aryllithium to XXII gives allylic alcohol XXIV. Oxidation ofXXIV with pyridinium chlorochromate affords the desired2,3-disubstituted cyclopentenone XXV. For preparation of compound XXV(R¹ ═SO₂ Me), 4-methylthiophenyllithium is used followed by oxidationwith the magesium salt of monoperoxyphthalic acid (MMPP) orm-chloroperoxybenzoic acid (mCPBA) to introduce the requiredmethylsulfonyl group in XXV. ##STR9## Method G

The sequence of Method G is the same as in Method F except R¹ containingacid chloride is used as starting material. R² is introduced at a laterstage via a carbonyl addition reaction, followed by PCC oxidation.##STR10## Method H

The 4,5-disubstituted isothiazoles and isothiazol-3(2H)-one-1,1-dioxides can be prepared by the general method described by B. Schulzeet al, Helvetica Chimica Acta, 1991, 74, 1059. Thus, aldehyde III (R^(a)═SO₂ Me) or XXVII is treated with excess NH₄ SCN in refluxing acetone toprovide the corresponding 4,5-disubstituted isothiazoles XXX and XXVIII,oxidation of which with hydrogen peroxide yields XXXI and XXIX.##STR11## Method I

An appropriately substituted aryl bromomethyl ketone is reacted with anappropriately substituted aryl acetic acid in a solvent such asacetonitrile in the presence of a base such as triethylamine and thentreated with 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU) to afford eitherthe lactone XXXIII or XXXV. ##STR12## Method J

Either of the lactones XXXIII or XXXV in a solvent such as THF isreacted with a reducing agent such as diisobutyl aluminium hydride orlithium borohydride at -78° C., to yield the furan XXXVI. ##STR13##Method K

The preparation of lactams XXXVII and XXXIX can be achieved by the samereaction as described in Method I, except an appropriate amide is used.##STR14## Method L

Methyl 2-hydroxy isobutyrate is silylated with TMSCl to give the TMSether XXXXI, which is treated with 4-methylthiophenyllithium to provideketone XXXXII. Desilylation followed by acylation yields keto-esterXXXXIV, which can be cyclized to lactone XXXXV by base catalysis.Oxidation of XXXXV with MMPP or mCPBA affords the desired productXXXXVI. ##STR15##

An alternative preparation of the hydroxy ketone XXXXIII is theoxidation of the known (J. Org. Chem. 1991 56, 5955-8; Sulfur Lett.1991, 12, 123-32) ketone XXXXIV. A mixture of XXXXIV, aquous base, suchas NaOH, organic solvents such as carbon tetrachloride/toluene and aphase transfer catalyst such as ALIQUAT 336 is stirred in air at roomtemperature to provide XXXXIII. Compound XXXXIII is also described inU.S. Pat. No. 4,321,118 and Org. Coat. 1986, 6, 175-95.

Representative Compounds

Tables I and II illustrate compounds of formula I.

                  TABLE I                                                         ______________________________________                                                             Example Method                                           ______________________________________                                         ##STR16##             1         A                                             ##STR17##             2         A                                             ##STR18##             3         A                                             ##STR19##             4         A                                             ##STR20##             5         A                                             ##STR21##             6         C                                             ##STR22##             7         F                                             ##STR23##             8         H                                             ##STR24##             9         I                                             ##STR25##             10        I                                             ##STR26##             11        J                                             ##STR27##             12        L                                             ##STR28##             13        A                                             ##STR29##             14        A                                             ##STR30##             15        I                                             ##STR31##             16        I                                             ##STR32##             17        I                                             ##STR33##             18        I                                             ##STR34##             19        I                                             ##STR35##             20        I                                             ##STR36##             21        I                                             ##STR37##             22        I                                             ##STR38##             23        I                                             ##STR39##             24        I                                             ##STR40##             25        I                                             ##STR41##             26        I                                             ##STR42##             27        I                                             ##STR43##             28        I                                             ##STR44##             29        I                                             ##STR45##             30        I                                             ##STR46##             31        I                                             ##STR47##             32        I                                             ##STR48##             33        I                                             ##STR49##             34        I                                             ##STR50##             35        I                                             ##STR51##             36        I                                             ##STR52##             37        I                                             ##STR53##             38        I                                             ##STR54##             39        I                                             ##STR55##             40        I                                             ##STR56##             41        I                                             ##STR57##             42        I                                             ##STR58##             43        I                                             ##STR59##             44        I                                             ##STR60##             45        I                                             ##STR61##             46        I                                             ##STR62##             47        I                                             ##STR63##             48        I                                             ##STR64##             49        I                                             ##STR65##             50        I                                             ##STR66##             51        I                                             ##STR67##             52        I                                             ##STR68##             53        I                                             ##STR69##             54        I                                             ##STR70##             55        H                                             ##STR71##             56        L + M                                         ##STR72##             57        L + M                                         ##STR73##             58        L + M                                         ##STR74##             59        L + M                                         ##STR75##             60        L + M                                        ______________________________________                                    

                  TABLE II                                                        ______________________________________                                         ##STR76##                                                                     ##STR77##                                                                     ##STR78##                                                                     ##STR79##                                                                     ##STR80##                                                                     ##STR81##                                                                     ##STR82##                                                                     ##STR83##                                                                     ##STR84##                                                                     ##STR85##                                                                     ##STR86##                                                                     ##STR87##                                                                     ##STR88##                                                                     ##STR89##                                                                     ##STR90##                                                                     ##STR91##                                                                     ##STR92##                                                                     ##STR93##                                                                     ##STR94##                                                                     ##STR95##                                                                     ##STR96##                                                                     ##STR97##                                                                     ##STR98##                                                                     ##STR99##                                                                     ##STR100##                                                                    ##STR101##                                                                    ##STR102##                                                                    ##STR103##                                                                    ##STR104##                                                                    ##STR105##                                                                    ##STR106##                                                                    ##STR107##                                                                    ##STR108##                                                                    ##STR109##                                                                    ##STR110##                                                                    ##STR111##                                                                    ##STR112##                                                                    ##STR113##                                                                    ##STR114##                                                                    ##STR115##                                                                    ##STR116##                                                                    ##STR117##                                                                    ##STR118##                                                                    ##STR119##                                                                    ##STR120##                                                                    ##STR121##                                                                    ##STR122##                                                                    ##STR123##                                                                    ##STR124##                                                                    ##STR125##                                                                    ##STR126##                                                                    ##STR127##                                                                    ##STR128##                                                                    ##STR129##                                                                    ##STR130##                                                                    ##STR131##                                                                    ##STR132##                                                                    ##STR133##                                                                    ##STR134##                                                                    ##STR135##                                                                    ##STR136##                                                                    ##STR137##                                                                    ##STR138##                                                                    ##STR139##                                                                    ##STR140##                                                                    ##STR141##                                                                    ##STR142##                                                                    ##STR143##                                                                    ##STR144##                                                                    ##STR145##                                                                    ##STR146##                                                                    ##STR147##                                                                    ##STR148##                                                                    ##STR149##                                                                    ##STR150##                                                                    ##STR151##                                                                    ##STR152##                                                                    ##STR153##                                                                    ##STR154##                                                                    ##STR155##                                                                    ##STR156##                                                                    ##STR157##                                                                    ##STR158##                                                                    ##STR159##                                                                    ##STR160##                                                                    ##STR161##                                                                    ##STR162##                                                                    ##STR163##                                                                    ##STR164##                                                                    ##STR165##                                                                    ##STR166##                                                                    ##STR167##                                                                    ##STR168##                                                                    ##STR169##                                                                    ##STR170##                                                                    ##STR171##                                                                    ##STR172##                                                                    ##STR173##                                                                   ______________________________________                                    

Assays for Determining Biological Activity

The compound of Formula I can be tested using the following assays todetermine their cyclooxygenase-2 inhibiting activity.

Inhibition of Cyclooxygenase Activity

Compounds were tested as inhibitors of cyclooxygenase activity in wholecell and microsomal cyclooxygenase assays. Both of these assays measuredprostaglandin E₂ (PGE₂) synthesis in response to arachidonic acid, usinga radioimmunoassay. Cells used for whole cell assays, and from whichmicrosomes were prepared for microsomal assays, were human osteosarcoma143 cells (which specifically express cyclooxygenase-2) and human U-937cells (which specifically express cyclooxygenase-1). In these assays,100% activity is defined as the difference between prostaglandin E₂synthesis in the absence and presence of arachidonate addition. IC₅₀values represent the concentration of putative inhibitor required toreturn PGE₂ synthesis to 50% of that obtained as compared to theuninhibited control. Representative results are shown in Table III.

Representative Rat Paw Edema Assay--Protocol

Male Sprague-Dawley rats (150-200 g) were fasted overnight and weregiven po either vehicle (5% tween 80 or 1% methocel) or a test compoundat 9-10 am. One hr later, a line was drawn using a permanent marker atthe level above the ankle in one hind paw to define the area of the pawto be monitored. The paw volume (V_(Oh)) was measured using aplethysmometer (Ugo-Basile, Italy) based on the principle of waterdisplacement. The animals were then injected subplantarly with 50 μl ofa 1% carrageenan solution in saline (FMC Corp, Maine) into the paw usingan insulin syringe with a 25-gauge needle (i.e. 500 ug carrageenan perpaw). Three hr later, the paw volume (V_(3h)) was measured and theincreases in paw volume (V_(3h) -V_(Oh)) were calculated. The animalswere euthanized by CO₂ aphyxiation and the absence or presence ofstomach lesions scored. Stomach scores were expressed as the sum oftotal lesions in mm. Paw edema data were compared with thevehicle-control group and percent inhibition calculated taking thevalues in the control group as 100%. Since a maximum of 60-70%inhibition (paw edema) was obtained with standard NSAIDs, ED₃₀ valueswere used for comparison. All treatment groups were coded to eliminateobserver bias. With this protocol, the ED₃₀ for Indomethacin is 1.0mg/kg. Representative results are shown in Table IV.

                  TABLE III*                                                      ______________________________________                                        Ex-  Whole Cells       Microsomes                                             am-  Conc.   COX-2    COX-1  Conc. COX-2  COX-1                               ple  (nM)    % inhib. % inhib.                                                                             (nM)  % inhib.                                                                             % inhib.                            ______________________________________                                         1   100     96       12     100   53      8                                   2   10      69       0       10   49     25                                   3   10      42               10   33     19                                   3   100     100             100   76     12                                   4                            10   47      2                                   5   10       0       0       10   43     31                                   6   100     78              100   19     16                                   7   100     74       0      1000  58     16                                   8   10      41                                                                8   100     89                                                                9   100     83              100   37      9                                  10   100     95              100   71     12                                  11   100     39              100   46      7                                  12   100     54                                                               13   10      41               10   52      7                                  13   100     84               10   58     10                                  14   10      73               10   45     29                                  14   100     89              100   63      0                                  14   1000    101             1000  69      0                                  15   20      39                                                               15   80      76                                                               15   160     95                                                               16   20      41                                                               16   40      50                                                               16   160     85                                                               17   40      41                                                               17   160     77                                                               18   40      24                                                               18   160     58                                                               19   40      21                                                               19   160     59                                                               20   10      70                                                               20   40      91                                                               21   10      50                                                               21   40      94                                                               22   20      39                                                               22   160     98                                                               23   20      50                                                               23   160     88                                                               24   40      43                                                               24   160     78                                                               25   160     40                                                               26   80      27                                                               26   160     39                                                               27   20      38                                                               27   160     97                                                               28   20      48                                                               28   160     69                                                               29   20      78                                                               29   160     85                                                               30   160     30                                                               31   20      49                                                               31   160     87                                                               32    5      43                                                               32   10      73                                                               32   40      92                                                               32   80      99                                                               33   160      6                                                               34   10      30                                                               34   40      80                                                               34   160     102                                                              35   20      32                                                               35   40      57                                                               35   160     83                                                               36   10      11                                                               36   40      50                                                               36   160     89                                                               37   10      53                                                               37   40      82                                                               37   160     93                                                               38   10      25                                                               38   40      63                                                               38   160     88                                                               39   10      17                                                               39   160     84                                                               40   10      43                                                               40   40      72                                                               40   160     96                                                               41                                                                            41                                                                            42   20      10                                                               42   160     44                                                               43   10      78                                                               43   40      101                                                              44   20      14                                                               44   40      55                                                               44   160     106                                                              45   10      16                                                               45   40      61                                                               45   160     101                                                              46   10      76                                                               46   40      94                                                               46   160     97                                                               47   10      61                                                               47   40      74                                                               47   160     101                                                              48   10       7                                                               48   160     47                                                               49   10      53                                                               49   40      91                                                               49   80      99                                                               50   80      42                                                               51    5      49                                                               51   20      95                                                               51   40      102                                                              52   10      50                                                               52   40      82                                                               52   160     102                                                              53   10      54                                                               53   40      96                                                               53   160     102                                                              54   10      81                                                               54   80      91                                                               54   160     99                                                               55   10      48                                                               55   80      59                                                               55   160     65                                                               ______________________________________                                         *In the whole cell assay Ibuprofen has an IC50 for COX1 of 1000 nM, and a     IC50 for COX2 of 3000 nM. Similarly, Indomethacin has an IC50 for COX1 of     100 nM, and an IC50 for COX2 of 10 nM.                                   

                  TABLE IV                                                        ______________________________________                                        ED30 (mg/kg)                                                                             STRUCTURE                                                          ______________________________________                                        ˜3.00                                                                               ##STR174##                                                        >10.00                                                                                    ##STR175##                                                        1.40                                                                                      ##STR176##                                                        2.80 (in 1% methocel) 0.72                                                                ##STR177##                                                        0.43                                                                                      ##STR178##                                                        ˜3.00                                                                               ##STR179##                                                        >3.00 3.00                                                                                ##STR180##                                                        1.10                                                                                      ##STR181##                                                        <0.30                                                                                     ##STR182##                                                        0.42                                                                                      ##STR183##                                                        0.034                                                                                     ##STR184##                                                        2.03                                                                                      ##STR185##                                                        1.49                                                                                      ##STR186##                                                        0.35                                                                                      ##STR187##                                                        0.33                                                                                      ##STR188##                                                        0.90                                                                                      ##STR189##                                                        0.38                                                                                      ##STR190##                                                        0.88                                                                                      ##STR191##                                                        0.47                                                                                      ##STR192##                                                        0.71                                                                                      ##STR193##                                                        ˜1.00                                                                               ##STR194##                                                        1.85                                                                                      ##STR195##                                                        0.22 0.23                                                                                 ##STR196##                                                        0.43                                                                                      ##STR197##                                                        2.17                                                                                      ##STR198##                                                        0.81                                                                                      ##STR199##                                                        0.68                                                                                      ##STR200##                                                        0.16                                                                                      ##STR201##                                                        ˜1.00                                                                               ##STR202##                                                        0.33                                                                                      ##STR203##                                                        0.46                                                                                      ##STR204##                                                        0.76                                                                                      ##STR205##                                                        0.48                                                                                      ##STR206##                                                        0.46                                                                                      ##STR207##                                                        0.26                                                                                      ##STR208##                                                        0.55                                                                                      ##STR209##                                                        0.25                                                                                      ##STR210##                                                        0.1-.3                                                                                    ##STR211##                                                        ˜0.10                                                                               ##STR212##                                                        0.13                                                                                      ##STR213##                                                        0.07                                                                                      ##STR214##                                                        ______________________________________                                    

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) all operations were carried out at room or ambient temperature, thatis, at a temperature in the range 18°-25° C.; evaporation of solvent wascarried out using a rotary evaporator under reduced pressure (600-4000pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60° C.; thecourse of reactions was followed by thin layer chromatography (TLC) andreaction times are given for illustration only; melting points areuncorrected and `d` indicates decomposition; the melting points givenare those obtained for the materials prepared as described; polymorphismmay result in isolation of materials with different melting points insome preparations; the structure and purity of all final products wereassured by at least one of the following techniques: TLC, massspectrometry, nuclear magnetic resonance (NMR) spectrometry ormicroanalytical data; yields are given for illustration only; whengiven, NMR data is in the form of delta (d) values for major diagnosticprotons, given in parts per million (ppm) relative to tetramethylsilane(TMS) as internal standard, determined at 300 MHz or 400 MHz using theindicated solvent; conventional abbreviations used for signal shape are:s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: inaddition "Ar" signifies an aromatic signal; chemical symbols have theirusual meanings; the following abbreviations have also been used v(volume), w (weight), b.p. (boiling point), m.p. (melting point), L(liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol(moles), mmol (millimoles), eq (equivalent(s)).

The following abbreviations have the indicated meanings:

Ac=acetyl

Bn=benzyl

DBU=1,8-diazabicyclo 5.4.0!undec-7-ene

DIBAL=diisobutylaluminum hydride

DMAP=4-(dimethylamino)pyridine

DMF=N,N-dimethylformamide

Et₃ N=triethylamine

LDA=lithium diisopropylamide

m-CPBA=metachloroperbenzoic acid

MMPP=monoperoxyphtalic acid

MPPM=monoperoxyphthalic acid, magnesium salt 6H₂ O

Ms=methanesulfonyl=mesyl=SO₂ Me

Ms0=methanesulfonate=mesylate

NSAID=non-steroidal anti-inflammatory drug

OXONE®=2KHSO₅.KHSO₄.K₂ SO₄

PCC=pyridinium chlorochromate

PDC=pyridinium dichromate

Ph=phenyl

Phe=benzenediyl

Pye=pyridinediyl

r.t.=room temperature

rac.=racemic

SAM=aminosulfonyl or sulfonamide or SO₂ NH₂

TBAF=tetra-n-butylammonium fluoride

Th=2- or 3-thienyl

TFAA=trifluoroacetic acid anhydride

THF=tetrahydrofuran

Thi=thiophenediyl

TLC=thin layer chromatography

TMS-CN=trimethylsilyl cyanide

Tz=1H (or 2H)-tetrazol-5-yl

C₃ H₅ =allyl

Alkyl Group Abbreviations

Me=methyl

Et=ethyl

n-Pr=normal propyl

i-Pr=isopropyl

n-Bu=normal butyl

i-Bu=isobutyl

s-Bu=secondary butyl

t-Bu=tertiary butyl

c-Pr=cyclopropyl

c-Bu=cyclobutyl

c-Pen=cyclopentyl

c-Hex=cyclohexyl

Example 13-(4-Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene

Step 1: 1-(4-Fluorophenyl)-2-(4-(methylthio)phenyl)ethanone

To 4-fluorobenzaldehyde (5.40 g) in 1,2-dichloroethane (43.50 mL) wereadded TMS-CN (4.32 g) and ZnI₂ (44 mg). After 0.5 h at r.t., the solventwas removed in vacuo. To the resulting TMS cyanohydrin (9.20 g) in THF(42.0 mL) at -78° C. was added dropwise a solution of LDA 0.51M in THF(88.9 mL). After a period of 0.5 h, a THF solution (30.0 mL) of4-(chloromethyl)thioanisole (9.93 g) was added dropwise over 0.5 h.After 18 h at +5° C., the resulting mixture was treated with TBAF (57.5mL) followed by a 25% aqueous solution of NH₄ OAc (100 mL) and extractedwith EtOAc (2×150 mL). After evaporation, a 10:1 mixture of Et₂ O andhexane (200 mL) was added to the crude ketone. After stirring for 10 hand filtration, the title product was obtained as a solid by filtration(2.40 g).

¹ H NMR (CD₃ COCD₃): d 2.45 (3H, s), 4.34 (2H, s), 7.19-7.29 (6H, m),8.14 (2H, q).

Step 2:Cis,trans-3-chloro-3-(4-fluorophenyl)-2-(4-(methylthio)phenyl)propenal

To a solution of 1-(4-fluorophenyl)-2-(4-(methylthio)phenyl ethanone(2.50 g) in 1,2-dichloroethane (27.0 mL) were introduced the Vilsmeierreagent (Aldrich catalog, 1992-1993) 3.3M (11.6 mL) and DMAP (1.17 g).After a period of 4 h at 80° C., the reaction mixture was extracted withEtOAc and 25% aqueous solution of NH₄ OAc. After evaporation in vacuoand drying for a few hours, the title product was used as such for thenext step.

¹ H NMR (CD₃ COCD₃): d 2.40 and 2.48 (3H, 2s), 6.90-7.80 (8H, m), 9.55(1H, s).

Step 3:5-(4-Fluorophenyl)-4-(4-(methylthio)phenyl)thiophene-2-carboxylic acidmethyl ester

To a solution of cis,trans3-chloro-3-(4-fluorophenyl)-2-(4-(methylthio)phenyl)propenal (3.00 g) inpyridine (12.0 mL) were added methyl thioglycolate (1.16 mL) and Et₃ N(4.09 mL). The resulting mixture was then heated at 80° C. for 2 h.After extraction with EtOAc and washing with 3N HCl, the title productwas purified by flash chromatography (30% EtOAc in hexane) (2.00 g).

¹ H NMR (CD₃ COCD₃): d 2.48 (3H, s), 3.88 (3H, s), 7.11 (2H, t), 7.21(4H, s), 7.37 (2H, q), 7.80 (1H, s).

Step 4:5-(4-Fluorophenyl)-4-(4-(methylsulfinyl)phenyl)thiophene-2-carboxylicacid methyl ester

To a solution of5-(4-fluorophenyl)-4-(4-(methylthio)phenyl)-thiophene-2-carboxylic acidmethyl ester (5.60 g) in CH₂ Cl₂ (84.0 mL) at 0° C. was addedportionwise m-CPBA 50 to 60% (5.39 g). After TLC showed completion (50%EtOAc in hexane), the reaction mixture was extracted with saturatedNaHCO₃, dried over Na2SO4, filtered and evaporated to dryness to providethe title compound as a white foam (5.00 g).

¹ H NMR (CD₃ COCD₃): d 2.75 (3H, s), 3.92 (3H, s), 7.15 (2H, t), 7.40(2H, q), 7.52 (2H, d), 7.66 (2H, d), 7.90 (1H, s).

Step 5:4-(4-(Aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxylicacid methyl ester

5-(4-Fluorophenyl)-4-(4-(methylsulfinyl)phenyl)thiophene-2-carboxylicacid methyl ester (0.500 g) was dissolved in TFAA (10.0 mL) and refluxedfor 0.5 h. The solvent was then removed in vacuo and the resultingresidue was co-evaporated 10 times with a Et₃ N--MeOH solution (1:1)(100.0 mL) to provide a viscous oil after pumping for a few hours. Theoil was dissolved in HOAc (10.0 mL) and treated at +10° C. with Cl₂ inHOAc (1.9M) (3.5 mL). After 20 min., the solvent was removed underreduced pressure and after pumping, THF (20.0 mL) was added to theresulting mass of product. After bubbling NH₃ through for a few minutesat 0° C., the reaction mixture was stirred for 0.5 h at r.t. Afterextraction with EtOAc--25% NH₄ OAc solution and flash chromatography (30to 40% EtOAc in hexane), the title product was obtained as a white solid(0.210 g).

¹ H NMR (CD₃ COCD₃): d 3,90 (3H, s), 6.55 (2H, bs), 7.13 (2H, t), 7.40(2H, q), 7.46 (2H, d), 7.83 (2H, d), 7.90 (1H, s).

Step 6:3-(4-Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene

To 4-(4-aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxylicacid methyl ester (0.460 g) in THF (5.70 mL) at 0° C. was added MeMgBr(1.4M) in toluene-THF solution (5.00 mL). The mixture was then stirredat r.t. for a few hours. The reaction was quenched by the addition of25% NH₄ OAc solution, extracted with EtOAc and dried over with Na₂ SO₄.The title compound was purified by flash chromatography (40 to 50% EtOAcin hexane) (0.300 g).

¹ H NMR (CD₃ COCD₃): d 1.65 (6H, s), 4.52 (1H, s), 6.55 (2H, bs), 7.09(3H, m), 7.34 (2H, dd), 7.30 (2H, m), 7.43 (2H, d), 7.82 (2H, d).

Anal. calcd. for C₁₉ H₁₈ FNO₃ S₂ ; C, 58.31; H, 4.60; N, 3.58. Found: C,57.94; H, 4.66; N, 3.44

Example 2 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene

Step 1:4-(4-(Aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxylicacid

To a solution of4-(4-(aminosulfonyl)phenyl)-5-(4-fluorophenyl)thiophene-2-carboxylicacid methyl ester (Example 1, Step 5) (0.210 g) in THF (2.0 mL) wereadded MeOH (1.0 mL), NaOH 1N (1.0 mL) and a few drops of NaOH 10N. Theresulting mixture was heated at 45° C. for 2 h and the reaction was thenpartitioned between EtOAc and HCl (3N) to provide the title product as awhite solid (0.200 g).

¹ H NMR (CD₃ COCD₃) d 6.60 (2H, s), 7.15 (2H, t), 7.35 (2H, q), 7.45(2H, d), 7.82 (2H, d), 7.87 (1H, s).

Step 2: 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene

To a solution of3-(4-(aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene-2-carboxylicacid (0.280 g) in quinoline (4.0 mL) was added Cu bronze (0.300 g).After 0.5 h at 180° C. under nitrogen, the reaction mixture wasextracted with EtOAc and HCl 3N, dried over Na₂ SO₄ and purified byflash chromatography (30% EtOAc in hexane) to give the title compound asa white solid (0.180 g).

¹ H NMR (CD₃ COCD₃): d 6.60 (2H, bs), 7.15 (2H, t), 7.29 (1H, d), 7.35(2H, q), 7.45 (2H, d), 7.60 (1H, d), 7.83 (2H, d).

Anal. calcd for C₁₆ H₁₂ FNO₂ S₂ ; C, 57.65; H, 3.60; N, 4.20. Found: C,57.62; H, 3.59; N, 4.15.

Example 33-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene

¹ H NMR (CD₃ COCD₃) d 1.40 (6H, d), 3.25 (1H, septuplet), 6.58 (2H, bs),7.05 (1H, s), 7.15 (2H, t), 7.32 (2H, dd), 7.46 (2H, d), 7.80 (2H, d).

Anal. calcd. for C₁₉ H₁₈ FNO₂ S₂. C, 60.80; H, 4.80; N, 3.73. Found: C,60.59; H, 4.45; N, 3.60.

Example 4 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene

¹ H NMR (CD₃)₂)CO) d 1.24-1.40 (3H, m), 1.40-1.56 (2H, m), 1.65-1.85(3H, m), 1.90-2.0 (2H, m), 3.18 (1H, m), 6.58 (2H, bs), 7.05 (1H, d),7.37 (1H, d), 7.58 (2H, d), 7.97 (2H, d).

Example 55-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylicacid

Step 1: 4-(2-(4-Methylthiophenyl)-1-oxo-ethyl)benzoic acid methyl ester

To methyl 4-formylbenzoate (10.30 g) in 1,2-dichloroethane at r.t. wereadded TMS-CN (6.58 mL) and ZnI₂ (2.00 g), after 0.5 h at r.t., thesolvent was removed in vacuo. To the resulting TMS cyanohyrin (5.00 g)in THF (22.0 mL) at -78° C. was added dropwise a solution of LDA 0.87Min THF (26.2 mL). After a period of 0.5 h, a THF solution (10.0 mL) of4-(chloromethyl)thioanisole was added dropwise over 0.5 h. Thetemperature was then brought slowly to -20° C. then to 5° C. for 2 h andTBAF 1M in THF (50.0 mL) was added. After the addition of 25% aqueoussolution of NH₄ OAc, the reaction mixture was extracted with EtOAc,dried over NASO₄, evaporated in vacuo and purified by flashchromatography (20 to 30% EtOAc in hexane) to afford the title compoundas a white solid (7.00 g).

Step 2: 4-(1-Oxo-2-(4-(methylsulfonyl)phenyl)ethyl) benzoic acid methylester

To 7.10 g of 4-(2-(4-methylthiophenyl)-1-oxo-ethyl)benzoic acid methylester in MeOH (100 mL) was added oxone (21.0 g) in H₂ O (20.0 mL) at 0°C. After a few hours at r.t., the reaction mixture was extracted withEtOAc and H₂ O to afford after flash chromatography (50 to 100% EtOAc inhexane), the title product as a white solid (3.20 g).

¹ H NMR (CD₃ COCD₃) d 3.10 (3H, s), 3.95 (3H, s), 4.65 (2H, s), 7.60(2H, d), 7.96 (2H, d), 8.20 (4H, q).

Step 3: Cis,trans4-(1-Chloro-3-oxo-2-(4-(methylsulfonyl)phenyl)-1-propenyl)benzoic acidmethyl ester

To a solution of 4-(1-oxo-2-((4-methylsulfonyl)phenyl)ethyl) benzoicacid (1.70 g) in 1,2-dichloroethane (15.0 mL) were added the Vilsmeierreagent 3.3M (6.2 mL) and DMAP (0.624 g). The resulting mixture washeated at 80° C. for 4 h. The reaction mixture was then extracted with25% aqueous solution of NH₄ OAc and EtOAc. After drying over Na₂ SO₄ andevaporation the title compound was obtained as an oil and used as suchfor the next step.

Step 4:5-(4-(Methoxycarbonyl)phenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylicacid methyl ester

Prepared from4-(1-chloro-3-oxo-2-(4-methylsulfonyl)phenyl)-1-propenyl)benzoic acidmethyl ester as for Example 1, Step 3.

¹ H NMR (CD₃ COCD₃) d 3.13 (3H, s), 3.85 and 3.92 (6H, 2s), 7.50 (2H,d), 7.55 (2H, d), 7.90 (2H, d), 7.92 (1H, s), 7.92 (2H, d).

Step 5:5-(4-(Carboxyphenyl)-4-(4-(methyl)sulfonyl)phenyl)thiophene-2-carboxylicacid

Prepared from5-(4-(methoxycarbonyl)phenyl)-4-(4-(methyl)sulfonyl)phenyl)thiophene-2-carboxylicacid methyl ester as for Example 2, Step 1.

¹ H NMR (CD₃ COCD₃) d 3.15 (3H; s), 7.50 (2H, d), 7.62 (2H, d), 7.95(2H, d), 7.98 (1H, s), 8.05 (2H, d).

Anal calcd. for C₁₉ H₁₄ O₆ S₂.0.1 H₂ O: C, 56.46; H, 3.51. Found: C,56.18; H, 3.51.

Example 64-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole

Step 1: 1-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone

To 1-(4-Fluorophenyl)-2-(4-(methylthio)phenyl)ethanone of Example 1,Step 1 (17.9 g) in a solution of CH₂ Cl₂ --MeOH (272.0 mL/27.0 mL) at 0°C. was added MPPM (28.0 g). The cooling bath was then removed and thereaction mixture stirred at r.t. for 1 h. At 0° C., additional MPPM(28.0 g) was added and the reaction mixture kept for 1.5 h at r.t. Theinsoluble material was filtered followed by evaporation of the solvents,the residue was then extracted with CH₂ Cl₂ --NaHCO₃. After evaporationin vacuo, the resulting solid was washed with ether-hexane (1:1) andfiltered to provide the title compound 16.8 g.

¹ H NMR (CD₃ COCD₃) d 3.13 (3H, s), 3.58 (2H, s), 7.29 (2H, t), 7.55(2H, d), 7.88 (2H, d), 8.20 (2H, dd).

Step 2: 2-Bromo-1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone

To 1-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.00 g) inCH₂ Cl₂ containing CHCl₃ (1.0 mL) and CCl₄ (1.0 mL) was added bromine(0.614 g). After shining light for 1 h, the reaction was quenched withNa₂ S₂ O₄, extracted with CH₂ Cl₂, dried over Na₂ SO₄ and evaporated toyield the title compound which was used as such for the next step (1.10g).

¹ H NMR (CD₃ COCD₃) d 3.10 (3H, s), 7.05 (1H, s), 7.30 (2H, t), 7.87(2H, d), 7.95 (2H, d), 8.25 (2H, dd).

Step 3:4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)-thiazole

To 2-bromo-1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-ethanone(1.10 g) in ethanol (15.0 mL) were added thioacetamide (0.266 g) andpyridine (0.300 mL). After refluxing for 2 h, the reaction mixture wasextracted with EtOAc, 25% NH₄ OAc and purified by flash chromatography(50% EtOAc in hexane then 90% Et₂ O in hexane) to yield the titlecompound (0.320 g).

¹ H NMR (CD₃ COCD₃) d 2.72 (3H, s), 3.15 (3H, s), 7.09 (2H, t), 7.52(2H, dd), 7.60 (2H, d), 7.92 (2H, d).

Anal. calcd. for C₁₇ H₁₄ FNO₂ S₂ : C, 58,78; H, 4.03; N, 4.03. Found: C,58.71, H, 4.17; N, 3.85.

Example 72-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one

Step 1: 1-(4-Fluorophenyl)-5-hexen-2-one

To a suspension of 14.6 g (80 mmol) of CdCl₂ in 200 mL of ether cooledto 0° C. was added 115 mL of 1.3M solution of 3-butene-1-magnesiumbromide dropwise. The mixture was refluxed for 1 h and ether was thenremoved by distillation. Benzene (500 mL) was introduced, followed by asolution of 17.5 g (100 mmol) 4-fluorophenylacetyl chloride. Afterrefluxing for 1 h, the reaction mixture was quenched with 200 mL ofsaturated aqueous NH₄ Cl, 50 mL of 1N HCl, and extracted with 200 mL of1:1 hexane/EtOAC. The organic phase was dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography elutedwith 4:1 hexane/EtOAc to give 15 g of the title product.

¹ H NMR (CDCl₃) d 2.40 (2H, t), 2.53 (2H, t), 3.63 (2H, s), 4.90-4.98(2H, m), 5.67-5.78 (1H, m), 6.98 (2H, t), 7.13 (2H, m).

Step 2: 1-(4-Fluorophenyl)-5-oxo-2-pentanone

A solution of 14 g of 1-(4-fluorophenyl)-5-hexen-2-one in 200 mL of 3:1CH₂ Cl₂ /MeOH was cooled to -78° C. and treated with excess ozone. Theresulting mixture was treated with 15 g of triphenylphosphine andstirred at room temperature for 1 h. The reaction mixture wasconcentrated and flash chromatographed with 3:1 hexane/EtOAc to give 8 gof the title ketoaldehyde.

¹ H NMR (CDCl₃) d 2.72 (4H, s), 3.71 (2H, s), 6.99 (2H, t), 7.14 (2H,m), 9.73 (1H, s).

Step 3: 2-(4-Fluorophenyl)-2-cyclopenten-1-one

A solution of 8 g of 1-(4-fluorophenyl)-5-oxo-2-pentanone in 300 mL ofMeOH was treated with 2 g of NaOMe. The mixture was stirred for 2 h andthen quenched with 5 mL of HOAc. The solvent was evaporated and theresidue purified by flash chromatography, eluting with 3:1 hexane/EtOActo give 7 g of the title product.

¹ H NMR (CDCl₃) d 2.57 (2H, m), 2.68 (2H, m), 7.04 (2H, J=8.8 Hz, t),7.67 (2H, J=8.8, 5.5 Hz, dd), 7.77 (1H, m).

Step 4: 1-(4-(Methylthio)phenyl)-2-(4-fluorophenyl)-2-cyclopenten-1-ol

To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et₂O cooled at -78° C., was added 22 mL of 1.7M solution of t-BuLi inpentane (38 mmol) dropwise. The reaction mixture was stirred for 15 minat -78° C. and a solution of 2.23 g of2-(4-Fluorophenyl)-2-cyclopenten-1-one in 10 mL of Et₂ O was added.After stirring for 15 min at -78° C., the reaction mixture was warmed to0° C., and quenched with 50 mL of sat. NH₄ Cl. The product was extractedwith 100 mL EtOAc, dried over Na₂ SO₄, and purified by flashchromatography, eluted with 4:1 hexane/EtOAc to give 3.4 g of thedesired product.

¹ H NMR (CDCl₃) d 2.12 (1H, s), 2.34 (2H, m), 2.44 (3H, s), 2.45-2.52(1H, m), 2.56-2.65 (1H, m), 6.37 (1H, m), 6.84 (2H, J=8.7 Hz, t), 7.17(2H, J=8.3 Hz, d), 7.24-7.33 (4H, m).

Step 5: 2-(4-Fluorophenyl)-3-(4-(methylthio)phenyl)-2-cyclopenten-1-one

To a suspension of PCC (4.5 g, 20.9 mmol) and 10 g of anhydrous 4 Åmolecular sieves in 150 mL of CH₂ Cl₂ was added a solution of 2.2 g (7.3mmol) of 1-(4-(methylthio)phenyl)-2-(4-fluorophenyl)-2-cyclopenten-1-olin 20 mL CH₂ Cl₂. The mixture was stirred for 1 h at r.t. and thendiluted with 300 mL of Et₂ O. After filtration and concentration, theresidue was flash chromatographed with 2:1 hexane/EtOAc to give 1.5 g ofthe title product.

¹ H NMR (CDCl₃) d 2.45 (3H, s), 2.68 (2H, m), 3.00 (2H, m), 7.02 (2H,J=8.6 Hz, t), 7.11 (2H, J=8.6 Hz, d), 7.15-7.23 (4H, m).

Step 6:2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one

To a solution of 50 mg (0.17 mmol) of2-(4-Fluorophenyl)-3-(4-methylthio)phenyl)-2-cyclopenten-1-one in 8 mLof 10:1 CH₂ Cl₂ /MeOH was added 124 mg (0.2 mmol) of MPPM. The reactionmixture was stirred at room temperature for 2 h and then diluted with 10mL of 1:1 hexane/EtOAc. After filtration and concentration, the residuewas purified by flash chromatography eluted with 2:1 EtOAc/hexane togive 45 mg of the title product.

¹ H NMR (acetone-d₆) d 2.67 (2H, m), 3.14 (3H, s), 3.16 (2H, m),7.05-7.10 (2H, m), 7.20-7.25 (2H, m), 7.63 (2H, d), 7.93 (2H, d).

Example 8 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole

To a solution of 338 mg (1 mmol) of cis,trans3-chloro-3-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)propenal in 5 mLof acetone was added 230 mg (3 mmol) of NH₄ SCN. The reaction mixturewas refluxed for 3 h, and then quenched with 20 mL of saturated NaHCO₃.The product was extracted with 100 mL of EtOAc, dried over Na₂ SO₄,concentrated and purified by flash chromatography eluted with 3:2hexane/EtOAc to give 250 mg of the title product.

¹ H NMR (CDCl₃) d 8.57 (1H, s), 7.93 (3H, d), 7.50 (2H, d), 7.30 (2H,t), 7.08 (2H, t).

Example 93-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Step 1: 2-Bromo-1-(4-(methylsulfonyl)phenyl)ethanone

A solution of 197 g of 4-(Methylthio)acetophenone (ref: JACS, 1952, 74,p. 5475) in 700 mL of MeOH and 3500 mL of CH₂ Cl₂ was added 881 g ofMMPP over a period of 30 min. After 3 h at room temperature the reactionmixture was filtered and the filtrate was washed with 2 L of saturatedaqueous solution of NaHCO₃ and 1 L of brine. The aqueous phase wasfurther extracted with 2 L of CH₂ Cl₂. The combined extracts was driedover Na₂ SO₄ concentrated to give 240 g of4-(methylsulfonyl)acetophenone as a white solid.

To a cooled (-5° C.) solution of 174 g of 4-(methylsulfonyl)acetophenonein 2.5 L of CHCl₃ was added 20 mg of AlCl₃, followed by a solution of 40mL of Br₂ in 300 mL CHCl₃. The reaction mixture was then treated with1.5 L of water and the CHCl₃ was separated. The aqueous layer wasextracted with 1 L of EtOAc. The combined extracts was dried over Na₂SO₄ and concentrated. The crude product was recystalized from 50/50EtOAc/hexane to give 210 g of2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone as a white solid.

Step 2

To the product of Step 1 (216 mg) dissolved in acetonitrile (4 mL) wasadded Et₃ N (0.26 mL), followed by 4-fluorophenylacetic acid (102 mg).After 1.5 h at room temperature 0.23 mL of DBU was added. The reactionmixture was stirred for another 45 min and then treated with 5 mL of 1NHCl. The product was extracted with EtOAc, dried over Na₂ SO₄ andconcentrated. The residue was purified by flash chromatography (40%EtOAc in hexane) to yield 150 mg of the title compound as a solid.

¹ H NMR (CD₃ COCD₃) d 3.15 (3H, s), 5.36 (3H, s), 7.18 (2H, J=8.9 Hz,t), 7.46 (2H, m), 7.7 (2H, J=8.65 Hz, d), 7.97 (2H, J=8.68, d).

Example 103-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone

¹ H NMR (CD₃ COCD₃) d 5.34 (2H, s), 6.67 (2H, bd), 7.18 (2H, m), 7.46(2H, m), 7.61 (2H, m), 7.90 (2H, m).

M.P. 187°-188° C. (d).

Example 11 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan

Step 1

Using the product of Example 10, (0.2 g) in THF (5 mL) and toluene (3mL) was added slowly at -78° C. a solution of DIBAL (0.72 mL, 1M intoluene). After 15 min, the solution was warmed up to 0° C. for another15 min. This mixture was then poured into a chilled aqueous solution ofsodium potassium tartrate and EtOAc. The organic layer was stirred for0.5 h with a few crystals of camphor sulfonic acid. This solution wasthen concentrated and purified by flash chromatography to yield thetitle compound.

¹ H NMR (CDCl₃)₋₋ 3.1 (3H, s), 7.02 (2H, J=8.9, t), 7.18 (2H, m), 7.4(2H, J=8.8 Hz, d), 7.58 (1H, s), 7.68 (1H, s), 7.85 (2H, J=8.8 Hz, d)

Example 125.5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone

Step 1: Methyl 2-trimethylsilyloxyisobutyrate

To a solution of 1.2 mL (10.4 mmol) of methyl 2-hydroxy-isobutyrate in50 mL of CH₂ Cl₂ were added 1.2 g (17.6 mmol) of imidazole and 2.1 mL(16.6 mmol) of TMSCl. The mixture was stirred at r.t. for 1.5 h andquenched with 20 mL of H₂ O. The organic layer was dried over MgSO₄,concentrated and passed through a short plug of silica gel eluted with9:1 hexane/EtOAc. Evaporation of solvent afforded 1.27 g of the titlecompound as a colorless oil.

¹ H NMR (CD₃ COCD₃) d 0.08 (9H, s), 1.38 (6H, s), 3.67 (3H, s).

Step 2: 2-Trimethylsilyloxy-4'-(methylthio)isobutyrophenone

A solution of 204 mg (1.0 mmol) of 4-bromothioanisole in 2.5 mL of THFwas cooled to -78° C. and treated with 0.42 mL of 2.5M n-BuLi solutionin hexane. After stirring at -78° C. for 1 h, a solution of 380 mg (2.0mmol) of methyl 2-trimethylsilyloxyisobutyrate in 2 mL of THF was added.The mixture was stirred at -78° C. for 2 h and then quenched with NH₄OAc buffer. The product was extracted with EtOAc, dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography, elutingwith 19:1 hexane/EtOAc to give 95 mg of the title product.

¹ H NMR (CD₃ COCD₃) d 0.05 (9H, s), 1.52 (6H, s), 2.53 (3H, s), 7.33(2H, d), 8.12 (2H, d).

Step 3: 2-Hydroxy-4'-(methylthio)isobutyrophenone

To a solution of 40 mg (0.14 mmol) of2-trimethylsilyloxy-4'-(methylthio)isobutyrophenone in 2 mL THF wasadded 0.2 mL of 1M n-Bu₄ NF in THF. The resulting mixture was stirredfor 30 min and then quenched with 10 mL of NH₄ OAc buffer. The productwas extracted with EtOAc, dried over MgSO₄ and concentrated. The residuewas purified by flash chromatography, eluting with 4:1 hexane/EtOAc togive 25 mg of the title product.

¹ H NMR (CD₃ COCD₃) d 1.50 (6H, s), 2.54 (3H, s), 4.68 (1H, s), 7.30(2H, d), 8.15 (2H, d).

Step 4: 2-(4-Fluorophenylacetoxy)-4'-(methylthio)isobutyrophenone

To a solution of 72 mg (0.34 mmol)2-hydroxy-4'-(methylthio)isobutyrophenone in 1.7 mL of CH₂ Cl₂ wereadded 0.2 mL of pyridine and 140 mg (0.81 mmol) of 4-fluorophenylacetylchloride. The mixture was stirred at room temperature overnight and thenquenched with NH₄ OAc buffer. The product was extracted with EtOAc,dried over MgSO₄ and concentrated. The crude product was purified byflash chromatography eluting with 8:1 hexane/EtOAc to give 95 mg of thetitle product.

¹ H NMR (CD₃ COCD₃) d 1.62 (3H, s), 1.67 (3H, s), 2.48 (3H, s), 3.79(2H, s), 7.0-7.3 (6H, m), 7.78 (2H, d).

Step 5:5,5-Dimethyl-3-(4-fluorophenyl-4-(4-methylthiophenyl)-2-(5H-furanone

To a solution of 95 mg of2-(4-fluorophenylacetoxy)-4'-(methylthio)-isobutyrophenone in 4 mL ofCH₂ Cl₂ was added 0.2 mL of 1,8-diazabicyclo(5.4.0)undec-7-ene. Themixture was stirred for 4 h and diluted with NH₄ OAc buffer. The productwas extracted with EtOAc, dried over MgSO₄ and concentrated. The residuewas purified by flash chromatography, eluting with 20:1 toluene/EtOAc togive 75 mg of the title product.

¹ H NMR (CD₃ COCD₃) d 1.58 (6H, s), 2.50 (3H, s), 7.03 (2H, dd),7.25-7.35 (4H, m), 7.41 (2H, dd).

Step 6:5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone

To a solution of 81 mg of5,5-dimethyl-3-(4-fluorophenyl)-4-(4-methyl-thiophenyl)-2-oxo-2H-dihydrofuranin 1.8 mL of CH₂ Cl₂ and 0.2 mL of MeOH was added 250 mg of MPPM. Thereaction mixture was stirred at room temperature for 1 h and thenquenched with aqueous NaHCO₃. The product was extracted with EtOAc,dried over MgSO₄ and concentrated. The crude product was purified byflash chromatography eluting with 1:1 hexane/EtOAc to give 73 mg of thetitle product.

¹ H NMR (CD₃ COCD₃) d 1.62 (6H, s), 3.15 (3H, s), 7.02 (2H, dd), 7.40(2H, dd), 7.65 (2H, d), 8.03 (2H, d).

Example 13 2-((4-aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene

¹ H NMR (CD₃ COCD₃) d 6.60 (2H, bs), 7.12 (2H, t), 7.25 (1H, d), 7.35(2H, m), 7.45 (2H, d), 7.65 (1H, d), 7.85 (2H, d).

Analysis calculated for C₁₆ H₁₂ FNS₂ O₂ C, 57.65; H, 3.60; N, 4.20Found: C, 57.55; H, 3.79; N, 4.03

Example 143-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene

¹ H NMR (300 MHz, CD₃ COCD₃) d 7.15 (2H, t), 7.30 (3H, m), 7.45 (2H, d),7.65 (1H, d), 7.95 (2H, d).

Example 153-(2,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ F₂ O₄ S C, 58.28; H, 3.45; S, 9.15Found: C, 58.27; H, 3.50; S, 9.27

Example 163-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

To a solution of 3,4-difluorophenylacetic acid (ALDRICH CHIMICAL) (10 g)and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (Example 9, Step 1)(17.3 g) in acetonitrile (200 mL) at room temperature was added slowlytriethylamine (20.2 mL). After 1 h at room temperature, the mixture wascooled in an ice bath and treated with 17.4 mL of DBU. After 2 h at 0°C., the mixture was treated with 200 mL of 1N HCl and the product wasextracted with EtOAc, dried over Na₂ SO₄ and concentrated. The residuewas applied on top of a silica gel plug (sintered glass funnel) elutedwith 75% EtOAc/hexane, giving after evaporation of the solvent and swishin ethyl acetate, 10 g of the title compound.

Analysis calculated for C₁₇ H₁₂ F₂ O₄ S C, 58.28; H, 3.45; S, 9.15Found: C, 58.02; H, 3.51; S, 9.35

Example 173-(2,6-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ F₂ O₄ S C, 58.28; H, 3.45; S, 9.15Found: C, 58.18; H, 3.50; S, 9.44

Example 183-(2.5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ F₂ O₄ S C, 58.28; H, 3.45; S, 9.15Found: C, 58.89; H, 3.51; S, 9.11

Example 19 3-(35-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ F₂ O₄ S C, 58.28; H, 3.45; S, 9.15Found: C, 58.27; H, 3.62; S, 9.32

Example 203-(4-Bromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₃ BrO₄ S C, 51.94; H, 3.33; S, 8.16 Found:C, 51.76; H, 3.42; S, 8.21

Example 213-(4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

¹ H NMR (300 MHz, CDCl₃) d 7.93 (2H, d), 7.49 (2H, d), 7.35 (4H, m),5.16 (2H, s), 3.06 (3H, s)

Example 223-(4-Methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈ H₁₆ O₅ S C, 62.78 H, 4.68; S, 9.31 Found: C,62.75; H, 4.72; S, 9.39

Example 23 3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

To a solution of phenylacetic acid (27.4 g, 201 mmol) and2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (Example 9, Step 1) (60 g,216 mmol, 1.075 eq.) in acetonitrile (630 mL) at 25° C. was added slowlytriethylamine (30.8 mL, 1.1 eq.). The mixture was stirred for 20 min. atroom temperature and then cooled in an ice bath. DBU (60.1 mL, 3 eq.)was slowly added. After stirring for 20 min. in the ice bath, thereaction was complete and the mixture was acidified with 1N HCl (colorchanges from dark brown to yellow). Then 2.4 L of ice and water wereadded, stirred for a few minutes, then the precipitate was filtered andrinsed with water (giving 64 g of crude wet product). The solid wasdissolved in 750 mL of dichloromethane (dried over MgSO₄, filtered) and300 g of silica gel was added. The solvent was evaporated to neardryness (silica gel a bit sticky) and the residue was applied on top ofa silica gel plug (sintered glass funnel) eluted with 10% EtOAc/CH₂ Cl₂,giving after evaporation of the solvent and swish in ethyl acetate, 36.6g (58%) of the title compound.

Analysis calculated for C₁₇ H₁₄ O₄ S C, 64.95; H, 4.49; S, 10.20 Found:C, 64.63; H, 4.65; S, 10.44

Example 243-(2-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₃ ClO₄ S C, 58.54; H, 3.76; S, 9.19 Found:C, 58.59; H, 3.80; S, 9.37

Example 253-(2-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ BrFO₄ S C, 49.75; H, 2.93 Found: C,49.75; H, 3.01

Example 263-(2-Bromo-4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

¹ H NMR (300 MHz, acetone-d₆) d 7.95 (2H, d), 7.85 (1H, d), 7.63 (2H,dd), 7.55 (1H, dd), 7.45 (1H, d), 5.50 (2H, s), 3.15 (3H, s)

Example 273-(4-Chloro-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

¹ H NMR (300 MHz, acetone-d₆) d 8.0 (2H, d), 7.70 (2H, d), 7.50-7.30(3H, m), 5.35 (2h, s), 3.15 (3H, s)

Example 283-(3-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ BrFO₄ S C, 49.75; H, 2.93 Found: C,49.44; H, 2.98

Example 293-(3-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₃ ClO₄ S C, 58.54; H, 3.76 Found: C,58.29; H, 3.76

Example 303-(2-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ ClFO₄ S C, 55.67; H, 3.30 Found: C,55.67; H, 3.26

Example 313-(2,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ Cl₂ O₄ S C, 53.28; H, 3.16; S, 8.37Found: C, 52.89; H, 3.23; S, 8.58

Example 323-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ Cl₂ O₄ S C, 53.28; H, 3.16; S, 8.37Found: C, 53.07; H, 3.32; S, 8.51

Example 333-(2,6-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ Cl₂ O₄ S C, 53.28; H, 3.16; S, 8.37Found: C, 52.99; H, 3.22; S, 8.54

Example 343-(3-Chloro-4-fluorophenyl)-4-(4-(methylsulfonylphenyl)-2-(5H)-furanone

¹ H NMR (300 MHz, acetone-d₆) d 8.0 (2H, d), 7.70 (2H, d), 7.60 (1H, d),7.25-7.40 (2H, m), 5.35 (2H, s), 3.15 (3H, s)

Example 353-(4-Trifluoromethylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

¹ H NMR (CD₃ COCD₃) d 8.10 (2H, d), 7.82-7.93 (4H, m), 7.75 (2H, d),5.55 (2H, s), 3.30 (3H, s)

Example 363-(3-Fluoro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈ H₁₅ FO₅ S C, 59.66; H, 4.17 Found: C, 59.92;H, 4.37

Example 373-(3-Chloro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈ H₁₅ ClO₅ S C, 57.07; H, 3.99 Found: C,57.29; H, 4.15

Example 383-(3-Bromo-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈ H₁₅ BrO₅ S C, 51.08; H, 3.57 Found: C,51.38; H, 3.62

Example 393-(2-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₃ FO₄ S C, 61.44; H, 3.94 Found: C, 61.13;H, 3.85

Example 403-(4-Methylthiophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

¹ H NMR (300 MHz, acetone-d₆) d 8.0 (2H, d), 7.70 (2H, d), 7.35 (2H, d),7.25 (2H, d), 5.35 (2H, s), 3.15 (3H, s), 2.55 (3H, s)

Example 413-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

¹ H NMR (300 MHz, CDCl₃) d 7.93 (2H, d), 7.49 (2H, d), 7.35 (1H, m),7.12 (3H, m), 5.18 (2H, s), 3.06 (3H, s)

Example 423-(2-Chloro-6-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

¹ H NMR (300 MHz, acetone-d₆), d 8.0 (2H, d), 7.70 (2H, d), 7.55-7.65(1H, m), 7.40 (1H, d), 7.30 (1H, m), 5.60 (2H, s), 3.15 (3H, s)

Example 433-(3-Bromo-4-methylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈ H₁₅ BrO₄ S C, 53.08; H, 3.71 Found: C,53.06; H, 3.83

Example 443-(4-Bromo-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ BrFO₄ S C, 49.65; H, 2.94 Found: C,49.76; H, 3.00

Example 45 3-(3,4-Dibromophenyl)-4-(4-(methylsulfonyl)phenyl-2-(5H)-furanone

₁ H NMR (300 MHz, acetone-d₆) d 8.0 (2H, d), 7.80 (1H, d), 7.75 (3H, m),7.25 (1H, d), 5.35 (2H, s), 3.15 (sH, s)

Example 463-(4-Chloro-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ ClFO₄ S C, 55.67; H, 3.30 Found: C,55.45; H, 3.30

Example 473-(4-Bromo-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ BrFO₄ S C, 49.66; H, 2.94; S, 7.80Found: C, 49.79; H, 3.01; S, 7.51

Example 483-(4-Bromo-2-chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇ H₁₂ BrClO₄ S C, 47.74; H, 2.83; S, 7.50Found: C, 47.92; H, 2.84; S, 7.42

Example 49 3-(2-Naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₂₁ H₁₆ O₄ S C, 69.22; H, 4.43 Found: C, 69.22;H, 4.46

Example 50 3-(7-Quinolinyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₂₀ H₁₅ NO₄ S C, 65.74; H, 4.14; N, 3.83 Found:C, 65.34; H, 4.40; N, 3.80

M.S. (DCI, CH₄) calculated for M⁺, 365 Found for M⁺ +1, 366

Example 513-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone

¹ H NMR (400 MHz, CD₃ COCD₃) d 7.92 (2H, dd), 7,64 (3H, dm), 7.60 (1H,dd), 7.32 (1H, dd), 6.70 (1H, bs), 5.38 (2H, s)

Example 523-(3,4-Difluorphenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone

₁ H NMR (400 MHZ, CD₃ COCD₃) d 7.92 (2H,dd), 7,64 (2H,dd), 7.30-7.45(2H,m), 7.22 (1H,m), 6.68 (2H, bs), 5.37 (2H,s)

Example 533-(3-Chloro-4-m,ethoxyphenyl)-4(4-aminosulfonyl)phenyl)-2-(2H)-furanone

Analysis calculated for C₁₇ H₁₄ CINO₅ S C, 53.76; H, 3.72, N, 3.69Found: C, 53.32; H, 3.84, N, 3.59

M.S. (Dcl, CH₄) calculated for M+,379 Found for M⁺ +1, 380

Example 543-(3-Bromo-4-methoxyphenyl)-4-(4-aminosulfonyl)phenyl)-2-(2H)-furanone

Analysis calculated fro C₁₇ H₁₄ BrNO₅ S C, 48.13; H, 3.33, N, 3.30Found: C, 48.26; H, 3.40, N, 3.28

M.S. (DCI, CH₄) calculated for M⁺, 423 Found for M⁺ +1, 424

In one aspect within this embodiment are the compounds of formula I##STR215## or pharmacetically acceptable salts thereof wherein:X--Y--Z-- is selected from the group consisting of --C(O)--O--CR⁵(R^(5'))-- when side b is a double bond, and sides a and c are singlebonds; and

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NH₂,

R² is selected from the group consisting of

(a) C₁₋₆ alkyl,

(b) C₃, C₄, C₅, C₆, and C₇, cycloalkyl,

(c) heteroaryl

(d) benzoheteroaryl

(e) mono- or di-substituted phenyl wherein the substituent is selectedfrom the group consisting of

(1) hydrogen,

(2) halo,

(3) C₁₋₆ alkoxy,

(4) C₁₋₆ alkylthio,

(5) CN,

(6) CF₃,

(7) C₁₋₆ alkyl,

(8) N₃,

(9) --CO₂ H,

(10) --CO₂ --C₁₋₄ alkyl,

(11) --C(R⁵)(R⁶)--OH,

(12) --C(R⁵)(R⁶)--O--C₁₋₄ alkyl, and

(13) --C₁₋₆ alkyl-CO₂ --R⁵ ;

R⁵, R^(5') and R⁶ are each independently selected from the groupconsisting of

(a) hydrogen,

(b) C₁₋₆ alkyl,

or R⁵ and R⁶ together with the carbon to which they are attached form asaturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.

An alternative genus encompases compounds of formula Ib ##STR216## or apharmaceutically acceptable salt thereof wherein: R¹ is selected fromthe group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NH₂,

(c) S(O)₂ NHC(O)CF₃,

(d) S(O)(NH)CH₃,

(e) S(O)(NH)NH₂,

(f) S(O)(NH)NHC(O)CF₃,

(g) P(O)(CH₃)OH, and

(h) P(O)(CH₃)NH₂,

R² is selected from the group consisting of

(a) C₃, C₄, C₅, C₆, and C₇, cycloalkyl,

(b) mono-, di- or tri-substituted phenyl wherein the substituent isselected from the group consisting of

(1) hydrogen,

(2) halo,

(3) C₁₋₆ alkoxy,

(4) C₁₋₆ alkylthio,

(5) CN,

(6) CF₃,

(7) C₁₋₆ alkyl,

(8) N₃,

(9) --CO₂ H,

(10) --CO₂ --C₁₋₄ alkyl,

(c) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is amonocyclic aromatic ring of 5 atoms, said ring having one hetero atomwhich is S, O, or N, and optionally 1, 2, or 3 additional N atoms; orthe heteroaryl is a monocyclic ring of 6 atoms, said ring having onehetero atom which is N, and optionally 1, 2 or 3 additional N atoms;said substituents are selected from the group consisting of

(1) hydrogen,

(2) halo, including fluoro, chloro, bromo and iodo,

(3) C₁₋₆ alkyl,

(4) C₁₋₆ alkoxy,

(5) C₁₋₆ alkylthio,

(6) CN,

(7) CF₃,

(8) N₃,

R⁵ and R^(5') are each independently selected from the group consistingof

(a) hydrogen,

(b) C₁₋₆ alkyl, with the proviso that at least one of R⁵ and R^(5') isC₁₋₆ alkyl.

Within this genus is the sub-genus of compounds wherein

R² is selected from the group consisting of

(a) cyclohexyl, and

(b) mono- or di-substituted phenyl, and wherein the substitutents areselected from the group consisting of

(1) hydrogen,

(2) halo,

(3) C₁₋₄ alkoxy,

(4) C₁₋₄ alkylthio,

(5) CN,

(6) CF₃,

(7) C₁₋₄ alkyl,

(8) N₃, and

R⁵ and R^(5'), R⁶, are each independently selected from the groupconsisting of

(a) hydrogen,

(b) methyl or ethyl, with the proviso that at least one of R⁵ and R^(5')is C₁₋₆ alkyl.

Within this sub-genus there is a class of compounds wherein

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NH₂,

(c) S(O)NHCH₃, and

(d) S(O)NHNH₂ ;

R² is mono or di-substituted phenyl wherein the substitutents areselected from the group consisting of

(1) hydrogen,

(2) halo, selected from the group consisting of fluoro, chloro andbromo,

(3) methoxy, and

(4) methyl.

Within this class is a sub-class of compounds wherein

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NH₂,

R² is mono or di-substituted phenyl wherein the substitutents areselected from the group consisting of

(1) hydrogen,

(2) halo, selected from the group consisting of fluoro, chloro andbromo;

R⁵ and R5' are each independently methyl.

Illustrating this sub-class are the compounds wherein

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

R² is mono or di-substituted phenyl wherein the substitutents are halo,selected from the group consisting of fluoro, chloro and bromo.

Exemplifying this sub-class are the compounds selected from

(1)5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(2)5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(3)5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(4)5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(5)5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(6)5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,

(7)5,5-Dimethyl-3-(2-naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,

or a pharmaceutically acceptable salt thereof, as well as ##STR217## ora pharmaceutically acceptable salt thereof.

In an alternative aspect the invention is directed to a method oftreating a disease in humans selected from stroke, cerebral ischemia andde-myelinating disorders which comprises administering to said human aneffective amount of a non-steroidal COX-2 inhibitor, wherein saidnon-steroidal COX-2 inhibitor will bind at least 100 times as well toCOX-2 as to COX-1.

An alternative preparation of the hydroxy ketone XLIII is the oxidationof the known (J. Org. Chem. 1991 56, 5955-8; Sulfur Lett. 1991, 12,123-32) ketone XLVII. A mixture of XLVII, aqueous base, such as NaOH,organic solvents such as carbon tetrachloride/toluene and a phasetransfer catalyst such as ALIQUAT 336 is stirred in air at roomtemperature to provide XLIII. Compound XLIII is also described in U.S.Pat. No. 4,321,118 and Org. Coat. 1986, 6, 175-95. ##STR218##

By reacting an acetylene XLVIII with carbon monoxide and water in thepresence of suitable catalysts, a mixture of compound XXXIII and itsisomer XXXV is obtained. The isomers are separable by standardprocedures in the art such as chromatography or crystallization.Examples of useful catalysts and conditions are PdCl₂ in aqueous HCl andEtOH, heated at 50°-150° C. and 50-150 atmospheres of pressure, or Rh₄(CO)₁₂ (or Rh₆ (CO)₁₆) in aqueous THF (or acetone, acetonitrile,benzene, toluene, EtOH, MeOH) containing a trialkylamine, at 50°-150° C.and 20-300 atmospheres pressure. See Takahashi et al., Organomettallics1991, 10, 2493-2498; and Tsuji et. al., J. Am. Chem. Soc. 1966, 88,1289-1292. ##STR219##

1,4-Addition to XLIX of 4-methylthiophenyl organometallic reagents L inthe presence of copper salts and the trapping of the resultant enolatewith trialkyl silyl chloride such as TMSCl or TIPSCl provide the keteneacetal LI. The ketene acetal can then be oxidized to the substitutedbutenolide LII by the method of Ito using catalytic amounts of Pd₂(OAC)₂ and Cu(OAc)₂ and O₂ in MeOH or by the method of Magnus usingPhIO/TMSN₃ and Bu₄ NF. Introduction of the iodine can be accomplished bytreating LII with I₂ in the presence of pyridine to afford LIII.Palladium catalyzed Susuki or Stille coupling of LIII with theappropriate aryl or alkyl partner such as the boronic acid LIV providesthe butenolide LV. The sulfide can be oxidized to a sulfone by variousoxidizing agents such as peracetic acid, MPPM, MMPP or H₂ O₂ to give thedesired compound LVI. See Y. Ito et. al., J. Am. Chem. Soc. 1979,101,494; and P. Magnus et. al., Tet. Lett. 1992, 2933. ##STR220##

Hydroxy ketone XLIII can be oxidized to the sulfone LVII by a suitableoxidizing agent such as OXONE^(R). By reacting the hydroxy sulfone LVIIwith an appropriately substituted aryl acetic acid in an inert solventin the presence of a dehydrating agent such as a carbodiimide and acatalytic amount of DMAP, ester LVIII can be obtained. Treatment ofester LVIII with a base such as DBU in an inert solvent affords thelactone LIX.

See also WO 95/00501, published Jan. 5, 1995, which is herebyincorporated by reference. ##STR221##

Example 55 5-(4-(Methylsulfonyl)phenyl)-4-(4-fluorophenyl)-isothiazole

M.S. (DCI, CH₄) calculated for M⁺, 333 Found for M⁺ +1, 334

Example 563-(3-Chlorophenyl)-5,5,-dimethyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

¹ H NMR (400 MHz, CDCl₃) d 8.00 (2H, d), 77.13-7.42 (6H, m), 3.08 (3H,s), 1.59 (6H, s).

Cox-1 (microsome) IC₅₀ >100 μM

Cox-2 (whole cell)IC₅₀ =31 nM

Example 575,5-Dimethyl-3-(2-naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₂₃ H₂₀ O₄ S C, 70.39; H, 5.19 Found: C, 69.99;H, 5.19

M.S. (DCI, CH₄) calculated for M⁺, 392 Found for M⁺ +1, 393

Cox-1. (microsome) IC₅₀ =approx. 50 μM

Cox-2 (whole cell)IC₅₀ =97 nM

Example 583-(3,4-Difluorophenyl)-5,5,-dimethyl-4-(4-(methylsulfonyl)phenyl)-2-(5H-furanone

Analysis calculated for C₁₉ H₁₆ F₂ O₄ S C, 60.31; H, 4.26; S, 8.47Found: C, 60.46; H, 4.34; S, 8.55

m.p. 191° C.

Cox-1 (microsome) IC₅₀ >1000 μM

Cox-2 (whole cell)IC₅₀ =13 nM

Example 593-(3,4-Dichlorophenyl)-5,5,-dimethyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₉ H₁₆ Cl₂ O₄ S C, 55.48; H, 3.92; S, 7.80Found: C, 55.65; H, 3.96; S, 8.04

m.p. 184°-185° C.

Cox-1 (microsome) IC₅₀ >1000 μM

Cox-2 (whole cell)IC₅₀ =13 nM

Example 603-(4-Chlorophenyl)-5,5,-dimethyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₉ H₁₇ ClO₄ S C, 60.56; H, 4.55 Found: C,60.44; H, 4.11

M.S. (DCI, CH₄) calculated for M⁺, 376 Found for M⁺ +1, 377

Cox-1 (microsome) IC₅₀ >100 μM

Cox-2 (whole cell)IC₅₀ =46 nM

Example 23

(alternative 1)

3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Into a 20 ml glass ampule are added 1 g of2-(4-(methylsulfonyl)phenyl)phenylacetylene, 20 mg of Rh₄ (CO)₁₂, 1.5 gof Et₃ N, 10 ml of THF, 1 ml of water under nitrogen atmosphere, and theampule is placed in a 100-ml stainless steel autoclave. The reactionsystem is flushed three times with CO then charged at room temperatureto a initial CO pressure of 100 atm. The reaction is carried at 100° C.for 5 h. The solution is then diluted with 50 ml of benzene and washedwith brine, 1N HCl. The benzene solution is dried over Na₂ SO₄, andconcentrated. The crude products are separated by column chromatographyon silica gel eluted with 2:1 EtOAc/hexane to give the title compoundand its regioisomer.

Example 23

(alternative 2)

3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Step 1: 2-trimethylsilyloxy-4-(4-(methylthio)phenyl)-3,4-dihydrofuran

To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et₂O cooled at -78° C., is added 22 mL of 1.7M solution of t-BuLi inpentane (38 mmol) dropwise. The reaction mixture is stirred for 15 minat -78° C. and 3.8 g of CuI is added and the reaction mixture is allowedto warm to -40° C. over a period of 30 min. A solution of 1.7 g of2(5H)-furanone in 10 ml of THF is added. After stirring for 1 h, 2 ml offreshly distilled TMSCl is added dropwise. The reaction mixture is thentreated with 2 ml of Et₃ N and 50 ml of sat. NaHCO₃, and extracted with100 ml of ether. The ether layer is dried over Na₂ SO₄ and concentratedto the crude title compound which is used for the next step withoutfurther purification.

Step 2: 4-(4-(methylthio)phenyl)-2-(5H)-furanone

To a solution of 4 g of Pd(OAc)2 in 100 ml of acetonitrile is addeddropwise the crude product from Step 1(5 g) under nitrogen at roomtemperature. After 10 h at room temperature, the mixture is condensedunder reduced pressure and the residue is purified by flashchromatography on silica gel eluted with 2:1 hexane/EtOAc to give thetitle compound.

Step 3: 3-iodo-4-(4-(methylthio)phenyl)-2-(5H)-furanone

To a solution of 3 g of the product of Step 2 in 30 ml of pyridine isadded 8.7 g of I₂. The mixture is stirred for 24 h and then diluted with200 ml of ether, washed with 100 ml of 5N HCl and 50 ml of 5N Na₂ S₂ O₃.The ether layer is dried over Na₂ SO₄ and concentrated to give the titlecompound.

Step 4: 3-(Phenyl)-4-(4-(methylthio)phenyl)-2-(5H)-furanone

A mixture of 4 g of the product of Step 3, 3.7 g of PhB(OH)₂, 0.4 g ofPh₃ As, 0.4 g of PdCl₂ (PhCN)₂ in 100 ml of benzene and 15 ml of 2N NaOHis refluxed for 6 h. Ether(200 ml) is then added and the mixture iswashed with 100 ml of saturated NaHCO₃. The organic layer is dried overMgSO₄ and concentrated. The residue is purified by flash chromatographyon silica gel eluted with 4:1 hexane/EtOAc to give the title compound.

Step 5: 3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

To a solution of 3 g of the product of Step 4 in 80 mL of 10:1 CH₂ Cl₂/MeOH is added 5.5 g of MPPM. The reaction mixture is stirred at roomtemperature for 2 h and then diluted with 100 mL of 1:1 hexane/EtOAc.After filtration and concentration, the residue is purified by flashchromatography eluted with 2:1 EtOAc/hexane to give the title product.

Example 615,5,-Dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Step 1 2-hydroxy-4-(methylsulfonyl)isobutyrophenone

To a solution of 2-hydroxy-4'-(methylthiol) isobutyrophenone (45 g) int-BuOH (500 mL) and CH₂ Cl₂ (200 mL) was added a solution of OXONE^(TM)(194 g) in H₂ O (1.4 L). The reaction mixture was stirred for 18 h atr.t. and then extracted with EtOAc (3×500 mL). The organic extracts werecombined and dried over Na₂ SO₄ and the solvent was evaporated. Theresidue was swished in ether/hexane to give the title compound as ayellow solid (47.4 g).

Step 2 3-Fluorophenylacetic acid,1,1-dimethyl-2-(4-(methylsulfonyl)phenyl)-2-oxo-ethyl ester

A mixture of 2-hydroxy-4'-(methylsulfonyl) isobutyrophenone (100 g),3-fluorophenylacetic acid (83 g),1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate(225 g) and DMAP (25 g) in CH₂ Cl₂ (2 L) was mechanically stirred for 17h at r.t. A solution of 1N HCl (1 L) was then added and the organicphase was separated, washed with a saturated solution of Na₂ CO₃ (0.4 L)and dried over MgSO₄. After concentration, the residue was purified bysilica gel chromatography, eluting with 30% EtOAc/hexane to give thetitle compound as a white solid (133 g).

Step35,5-Dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl))-2-(5H)-furanone

A solution of the product from Step 2 (120 g) in CH₂ Cl₂ (1 L) wastreated with DBU (81.6 g) and stirred for 1 h at r.t. The reactionmixture was then treated with 1N HCl (550 mL) and the organic phase wasseparated, washed with saturated NaHCO₃ and dried over MgSO₄. Afterconcentration, the crude was swished from 20% EtOAc/hexane (450 mL) togive the title compound as a white solid (108.4 g, m.p. 172.7° C.).

Analysis Calculated C 63.32; H 4.75 Found: C 63.50; H 4.79

Cox-1 (microsome) IC₅₀ >100 μM

Cox-2 (whole cell)IC₅₀ 37 nM

Rat pyresis ED₅₀ =1.47

What is claimed is:
 1. A method of treating Alzheimer's disease in ahuman which comprises administering to said human an effective amount ofa non-steroidal COX-2 inhibitor, wherein said non-steroidal COX-2inhibitor will bind at least 100 times as well to COX-2 as to COX-1. 2.A method according to claim 1 wherein the administration is oraladministration.
 3. A method according to claim 2 wherein thenon-steroidal COX-2 inhibitor is within a tablet or capsule.
 4. A methodaccording to claim 3 wherein said COX-2 inhibitor is selected from:(a)3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene,(b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, (c)3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene,(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene, (e)5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl) thiophene-2-carboxylicacid, (f)4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole, (g)2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (h)4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole, (i)3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (j)3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone, (k)3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl) furan, (l)5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (m)2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl) thiophene, (n)3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (p)5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (q)5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (r)3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (s)3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (t)5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,(u)5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,(v)5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,(w) 3-(2-Naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (x)5,5-Dimethyl-3-(2-naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, and (y)3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.
 5. A method oftreating dementia associated with Alzheimer's disease in a human whichcomprises administering to said human an effective amount of anon-steroidal COX-2 inhibitor, wherein said non-steroidal COX-2inhibitor will bind at least 100 times as well to COX-2 as to COX-1. 6.A method according to claim 5 wherein the administration is oraladministration.
 7. A method according to claim 6 wherein thenon-steroidal COX-2 inhibitor is within a tablet or capsule.
 8. A methodaccording to claim 7 wherein the COX-2 inhibitor is selected from:(a)3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene,(b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, (c)3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene,(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene, (e)5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl) thiophene-2-carboxylicacid, (f)4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole, (g)2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (h)4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole, (i)3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (j)3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone, (k)3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl) furan, (l)5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (m)2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl) thiophene, (n)3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (p)5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (q)5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (r)3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (s)3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (t)5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,(u)5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,(v)5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,(w) 3-(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (x)5,5-Dimethyl-3-(2-naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, and (y)3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.
 9. A methodaccording to claim 1 wherein the COX-2 inhibitor is of formula I##STR222## or pharmacetically acceptable salts thereof wherein:X--Y--Z-- is selected from the group consisting of --C(O)--O--CR⁵(R^(5'))-- when side b is a double bond, and sides a and c are singlebonds; andR¹ is selected from the group consisting of(a) S(O)₂ CH₃, (b)S(O)₂ NH₂, R² is selected from the group consisting of(a) C₁₋₆ alkyl,(b) C₃, C₄, C₅, C₆, and C₇, cycloalkyl, (c) heteroaryl (d) mono- ordi-substituted phenyl wherein the substituent is selected from the groupconsisting of(1) hydrogen, (2) halo, (3) C₁₋₆ alkoxy, (4) C₁₋₆alkylthio, (5) CN, (6) CF₃, (7) C₁₋₆ alkyl, (8) N₃, (9) --CO₂ H, (10)--CO₂ --C₁₋₄ alkyl, (11) --C(R⁵)(R⁶)--OH, (12) --C(R⁵)(R⁶)--O--C₁₋₄alkyl, and (13) --C₁₋₆ alkyl-CO₂ --R⁵ ; R⁵, R^(5') and R⁶ are eachindependently selected from the group consisting of(a) hydrogen, (b)C₁₋₆ alkyl,or R⁵ and R⁶ together with the carbon to which they areattached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7atoms.